2024/11/13 更新

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写真a

マツモリ ノブアキ
松森 信明
MATSUMORI NOBUAKI
所属
理学研究院 化学部門 教授
理学部 化学科(併任)
理学府 化学専攻(併任)
職名
教授
連絡先
メールアドレス
電話番号
0928024153
プロフィール
膜タンパク質を含む生体膜の統合理解を目指し、分析化学ばかりでなく、生物物理、有機化学、ケミカルバイオロジーや構造生物学の手法を導入し、多角的な研究を行っている。具体的には、脂質ラフトや多様な脂質多様性といった脂質膜そのものの理解を目指すとともに、麻酔薬のような脂質膜に作用する薬剤の機構解析も行う。 学部および大学院では、分析化学教育を行っている。
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研究分野

  • ライフサイエンス / 生物有機化学

  • ナノテク・材料 / 生物分子化学

  • ナノテク・材料 / 生体化学

  • ナノテク・材料 / 構造有機化学、物理有機化学

  • ナノテク・材料 / 分析化学

  • ナノテク・材料 / ケミカルバイオロジー

▼全件表示

学位

  • 博士(理学)

経歴

  • 九州大学 大学院理学府化学専攻 教授 

    2014年7月 - 現在

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  • 東京大学大学院農学生命学研究科 学振研究員 大阪大学大学院理学研究科 助手 大阪大学大学院理学研究科 助教 大阪大学大学院理学研究科 准教授   

研究テーマ・研究キーワード

  • 研究テーマ: 膜タンパク質

    研究キーワード: 膜タンパク質

    研究期間: 2024年

  • 研究テーマ: 脂質ラフト

    研究キーワード: 脂質ラフト

    研究期間: 2024年

  • 研究テーマ: 脂質ケミカルバイオロジー

    研究キーワード: 脂質ケミカルバイオロジー

    研究期間: 2024年

  • 研究テーマ: 生物有機化学

    研究キーワード: 生物有機化学

    研究期間: 2024年

  • 研究テーマ: 生体膜

    研究キーワード: 生体膜

    研究期間: 2024年

  • 研究テーマ: 生体分析化学

    研究キーワード: 生体分析化学

    研究期間: 2024年

  • 研究テーマ: ケミカルバイオロジー

    研究キーワード: ケミカルバイオロジー

    研究期間: 2024年

  • 研究テーマ: NMR

    研究キーワード: NMR

    研究期間: 2024年

  • 研究テーマ: 生体分析化学

    研究キーワード: 生体膜、機器分析、バイオ分析

    研究期間: 2014年7月 - 2024年12月

受賞

  • 井上研究奨励賞

    1998年2月   井上科学振興財団   遠隔 C-H 核スピン結合定数を用いた天然物鎖状構造の立体配置決定

論文

  • Raft-based sphingomyelin interactions revealed by new fluorescent sphingomyelin analogs 査読 国際誌

    Masanao Kinoshita, Kenichi G.N. Suzuki, Nobuaki Matsumori, Misa Takada, Hikaru Ano, Kenichi Morigaki, Mitsuhiro Abe, Asami Makino, Toshihide Kobayashi, Koichiro M. Hirosawa, Takahiro K. Fujiwara, Akihiro Kusumi, Michio Murata

    Journal of Cell Biology   216 ( 4 )   1183 - 1204   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sphingomyelin (SM) has been proposed to form cholesterol-dependent raft domains and sphingolipid domains in the plasma membrane (PM). How SM contributes to the formation and function of these domains remains unknown, primarily because of the scarcity of suitable fluorescent SM analogs. We developed new fluorescent SM analogs by conjugating a hydrophilic fluorophore to the SM choline headgroup without eliminating its positive charge, via a hydrophilic nonaethylene glycol linker. The new analogs behaved similarly to the native SM in terms of their partitioning behaviors in artificial liquid order-disorder phase-separated membranes and detergent-resistant PM preparations. Single fluorescent molecule tracking in the live-cell PM revealed that they indirectly interact with each other in cholesterol- and sphingosine backbone-dependent manners, and that, for ~10-50 ms, they undergo transient colocalization-codiffusion with a glycosylphosphatidylinositol (GPI)-anchored protein, CD59 (in monomers, transient-dimer rafts, and clusters), in CD59-oligomer size-, cholesterol-, and GPI anchoring-dependent manners. These results suggest that SM continually and rapidly exchanges between CD59-associated raft domains and the bulk PM.

    DOI: 10.1083/jcb.201607086

  • Orientation and Order of the Amide Group of Sphingomyelin in Bilayers Determined by Solid-State NMR 査読 国際誌

    松森 信明

    BIOPHYSICAL JOURNAL   108 ( 12 )   2015年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bpj.2015.05.011

  • Deuterium NMR of Raft Model Membranes Reveals Domain-Specific Order Profiles and Compositional Distribution 査読 国際誌

    松森 信明

    BIOPHYSICAL JOURNAL   108 ( 10 )   2015年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bpj.2015.04.008

  • Axial Hydrogen at C7 Position and Bumpy Tetracyclic Core Markedly Reduce Sterol's Affinity to Amphotericin B in Membrane. 査読 国際誌

    松森 信明

    Biochemistry   51 ( 42 )   2014年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1021/bi3009399

  • Detailed Comparison of Deuterium Quadrupole Profiles between Sphingomyelin and Phosphatidylcholine Bilayers 査読 国際誌

    松森 信明

    BIOPHYSICAL JOURNAL   106 ( 3 )   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bpj.2013.12.034

  • Mode of molecular interaction of triterpenoid saponin ginsenoside Rh2 with membrane lipids in liquid-disordered phases

    Garza-Miyazato, D; Hanashima, S; Umegawa, Y; Murata, M; Kinoshita, M; Matsumori, N; Greimel, P

    BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES   1866 ( 7 )   184366 - 184366   2024年10月   ISSN:0005-2736 eISSN:1879-2642

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biochimica et Biophysica Acta - Biomembranes  

    Ginsenoside Rh2 (Rh2) is a ginseng saponin comprising a triterpene core and one unit of glucose and has attracted much attention due to its diverse biological activities. In the present study, we used small-angle X-ray diffraction, solid-state NMR, fluorescence microscopy, and MD simulations to investigate the molecular interaction of Rh2 with membrane lipids in the liquid-disordered (Ld) phase mainly composed of palmitoyloleoylphosphatidylcholine compared with those in liquid-ordered (Lo) phase mainly composed of sphingomyelin and cholesterol. The electron density profiles determined by X-ray diffraction patterns indicated that Rh2 tends to be present in the shallow interior of the bilayer in the Ld phase, while Rh2 accumulation was significantly smaller in the Lo phase. Order parameters at intermediate depths in the bilayer leaflet obtained from 2H NMR spectra and MD simulations indicated that Rh2 reduces the order of the acyl chains of lipids in the Ld phase. The dihydroxy group and glucose moiety at both ends of the hydrophobic triterpene core of Rh2 cause tilting of the molecular axis relative to the membrane normal, which may enhance membrane permeability by loosening the packing of lipid acyl chains. These features of Rh2 are distinct from steroidal saponins such as digitonin and dioscin, which exert strong membrane-disrupting activity.

    DOI: 10.1016/j.bbamem.2024.184366

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  • Highly sensitive two-dimensional profiling of N-linked glycans by hydrophilic interaction liquid chromatography and dual stacking capillary gel electrophoresis

    Miki, T; Yamamoto, S; Liu, CC; Torikai, K; Kinoshita, M; Matsumori, N; Kawai, T

    ANALYTICA CHIMICA ACTA   1320   342990 - 342990   2024年9月   ISSN:0003-2670 eISSN:1873-4324

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Analytica Chimica Acta  

    Background: N-Glycosylation is one of the most important post-translational modifications in proteins. As the N-glycan profiles in biological samples are diverse and change according to the pathological condition, various profiling methods have been developed, such as liquid chromatography (LC), capillary electrophoresis (CE), and mass spectrometry. However, conventional analytical methods have limitations in sensitivity and/or resolution, hindering the discovery of minor but specific N-glycans that are important both in the basic glycobiology research and in the medical application as biomarkers. Therefore, a highly sensitive and high-resolution N-glycan profiling method is required. Results: In this study, we developed a novel two-dimensional (2D) separation system, which couples hydrophilic interaction liquid chromatography (HILIC) with capillary gel electrophoresis (CGE) via large-volume dual preconcentration by isotachophoresis and stacking (LDIS). Owing to the efficient preconcentration efficiency of LDIS, limit of detection reached 12 pM (60 amol, S/N = 3) with good calibration curve linearity (R2 > 0.999) in the 2D analysis of maltoheptaose. Finally, 2D profiling of N-glycans obtained from standard glycoproteins and cell lysates were demonstrated. High-resolution 2D profiles were successfully obtained by data alignment using triple internal standards. N-glycans were well distributed on the HILIC/CGE 2D plane based on the glycan size, number of sialic acids, linkage type, and so on. As a result, specific minor glycans were successfully identified in HepG2 and HeLa cell lysates. Significance and novelty: In conclusion, the HILIC/CGE 2D analysis method showed sufficient sensitivity and resolution for identifying minor but specific N-glycans from complicated cellular samples, indicating the potential as a next-generation N-glycomics tool. Our novel approach for coupling LC and CE can also dramatically improve the sensitivity in other separation modes, which can be a new standard of 2D bioanalysis applicable not only to glycans, but also to other diverse biomolecules such as metabolites, proteins, and nucleic acids.

    DOI: 10.1016/j.aca.2024.342990

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  • Identification of lipid-specific proteins with high-density lipid-immobilized beads

    Morito, M; Yasuda, H; Matsufuji, T; Kinoshita, M; Matsumori, N

    ANALYST   149 ( 14 )   3747 - 3755   2024年7月   ISSN:0003-2654 eISSN:1364-5528

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Analyst  

    In biological membranes, lipids often interact with membrane proteins (MPs), regulating the localization and activity of MPs in cells. Although elucidating lipid-MP interactions is critical to comprehend the physiological roles of lipids, a systematic and comprehensive identification of lipid-binding proteins has not been adequately established. Therefore, we report the development of lipid-immobilized beads where lipid molecules were covalently immobilized. Owing to the detergent tolerance, these beads enable screening of water-soluble proteins and MPs, the latter of which typically necessitate surfactants for solubilization. Herein, two sphingolipid species—ceramide and sphingomyelin—which are major constituents of lipid rafts, were immobilized on the beads. We first showed that the density of immobilized lipid molecules on the beads was as high as that of biological lipid membranes. Subsequently, we confirmed that these beads enabled the selective pulldown of known sphingomyelin- or ceramide-binding proteins (lysenin, p24, and CERT) from protein mixtures, including cell lysates. In contrast, commercial sphingomyelin beads, on which lipid molecules are sparsely immobilized through biotin-streptavidin linkage, failed to capture lysenin, a well-known protein that recognizes clustered sphingomyelin molecules. This clearly demonstrates the applicability of our beads for obtaining proteins that recognize not only a single lipid molecule but also lipid clusters or lipid membranes. Finally, we demonstrated the screening of lipid-binding proteins from Neuro2a cell lysates using these beads. This method is expected to significantly contribute to the understanding of interactions between lipids and proteins and to unravel the complexities of lipid diversity.

    DOI: 10.1039/d4an00579a

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  • Gold nanoparticle-powered screening of membrane protein-specific lipids from complex lipid mixtures 査読 国際誌

    Wangamnuayporn, S; Kinoshita, M; Kawai, T; Matsumori, N

    ANALYTICAL BIOCHEMISTRY   687   115447   2024年4月   ISSN:0003-2697 eISSN:1096-0309

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    記述言語:その他   掲載種別:研究論文(学術雑誌)   出版者・発行元:Analytical Biochemistry  

    Membrane proteins (MPs) are affected by binding of specific lipids. We previously developed a methodology for systematically analyzing MP-lipid interactions leveraging surface plasmon resonance (SPR). In this method, the gold sensor chip surface was modified with a self-assembled monolayer (SAM), which allowed for a larger amount of MP-immobilization. However, the laborious lipid purification step remained a bottleneck. To address this issue, a new strategy has been developed utilizing gold nanoparticles (AuNPs) instead of the gold sensor chip. AuNPs were coated with SAM, on which MP was covalently anchored. The MP-immobilized AuNPs were mixed with a lipid mixture, and the recovered lipids were quantified by LC–MS. Bacteriorhodopsin (bR) was used as an MP to demonstrate this concept. We optimized immobilization conditions and confirmed the efficient immobilization of bR by dynamic light scattering and electron micrographs. Washing conditions for pulldown experiments were optimized to efficiently remove non-specific lipids. A new binding index was introduced to qualitatively reproduce the known affinity of lipids for bR. Consequently, the low-abundant and least-studied lipid S-TeGD was identified as a candidate for bR-specific lipids. This technique can skip the laborious lipid purification process, accelerating the screening of MP-specific lipids from complex lipid mixtures.

    DOI: 10.1016/j.ab.2023.115447

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  • Truncated derivatives of amphidinol 3 reveal the functional role of polyol chain in sterol-recognition and pore formation 査読 国際誌

    Matsumori, N; Hieda, M; Morito, M; Wakamiya, Y; Oishi, T

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   98   129594   2024年1月   ISSN:0960-894X eISSN:1464-3405

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    記述言語:その他   掲載種別:研究論文(学術雑誌)   出版者・発行元:Bioorganic and Medicinal Chemistry Letters  

    Here we examined the membrane binding and pore formation of amphidinol 3 (AM3) and its truncated synthetic derivatives. Importantly, both of the membrane affinity and pore formation activity were well correlated with the reported antifungal activity. Our data clearly demonstrated that the C1-C30 moiety of AM3 plays essential roles both in sterol recognition and stable pore formation. Based on the current findings, we updated the interacting model between AM3 and sterol, in which the moiety encompassing from C21 to C67 accommodates a sterol molecule with forming hydrogen bonds with the sterol hydroxy group and van der Waals contact between AM3 polyol and sterol skeleton. Although the conformation of the C1-C20 moiety of AM3 is hard to specify due to its flexibility, the region likely contributes to stabilization of pore structure.

    DOI: 10.1016/j.bmcl.2023.129594

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  • Cardiolipin binding enhances KcsA channel gating via both its specific and dianion-monoanion interchangeable sites 査読 国際誌

    Iwamoto, M; Morito, M; Oiki, S; Nishitani, Y; Yamamoto, D; Matsumori, N

    ISCIENCE   26 ( 12 )   108471 - 108471   2023年12月   ISSN:2589-0042 eISSN:2589-0042

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    記述言語:その他   掲載種別:研究論文(学術雑誌)   出版者・発行元:iScience  

    KcsA is a potassium channel with a plethora of structural and functional information, but its activity in the KcsA-producing actinomycete membranes remains elusive. To determine lipid species involved in channel-modulation, a surface plasmon resonance (SPR)-based methodology, characterized by immobilization of membrane proteins under a membrane environment, was applied. Dianionic cardiolipin (CL) showed extremely higher affinity for KcsA than monoanionic lipids. The SPR experiments further demonstrated that CL bound not only to the N-terminal M0 helix, a lipid-sensor domain, but to the M0 helix-deleted mutant. In contrast, monoanionic lipids interacted primarily with the M0 helix. This indicates the presence of an alternative CL-binding site, plausibly in the transmembrane domain. Single-channel recordings demonstrated that CL enhanced channel opening in an M0-independent manner. Taken together, the action of monoanionic lipids is exclusively mediated by the M0 helix, while CL binds both the M0 helix and its specific site, further enhancing the channel activity.

    DOI: 10.1016/j.isci.2023.108471

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  • Variational autoencoder-based chemical latent space for large molecular structures with 3D complexity 査読 国際誌

    Ochiai, T; Inukai, T; Akiyama, M; Furui, K; Ohue, M; Matsumori, N; Inuki, S; Uesugi, M; Sunazuka, T; Kikuchi, K; Kakeya, H; Sakakibara, Y

    COMMUNICATIONS CHEMISTRY   6 ( 1 )   249   2023年11月   ISSN:2399-3669

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    記述言語:その他   掲載種別:研究論文(学術雑誌)   出版者・発行元:Communications Chemistry  

    The structural diversity of chemical libraries, which are systematic collections of compounds that have potential to bind to biomolecules, can be represented by chemical latent space. A chemical latent space is a projection of a compound structure into a mathematical space based on several molecular features, and it can express structural diversity within a compound library in order to explore a broader chemical space and generate novel compound structures for drug candidates. In this study, we developed a deep-learning method, called NP-VAE (Natural Product-oriented Variational Autoencoder), based on variational autoencoder for managing hard-to-analyze datasets from DrugBank and large molecular structures such as natural compounds with chirality, an essential factor in the 3D complexity of compounds. NP-VAE was successful in constructing the chemical latent space from large-sized compounds that were unable to be handled in existing methods, achieving higher reconstruction accuracy, and demonstrating stable performance as a generative model across various indices. Furthermore, by exploring the acquired latent space, we succeeded in comprehensively analyzing a compound library containing natural compounds and generating novel compound structures with optimized functions.

    DOI: 10.1038/s42004-023-01054-6

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  • Impact of sphingomyelin acyl chain heterogeneity upon properties of raft-like membranes 査読 国際誌

    Hirano, K; Kinoshita, M; Matsumori, N

    BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES   1864 ( 12 )   184036 - 184036   2022年12月   ISSN:0005-2736 eISSN:1879-2642

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biochimica et Biophysica Acta - Biomembranes  

    Sphingomyelin (SM) is a main component of lipid rafts and characteristic of abundance of long and saturated acyl chains. Recently, we reported that fluorescence-labeled lipids including C16:0 and C18:0SMs retained membrane behaviors of inherent lipids. Here, we newly prepared fluorescent SMs with longer acyl chains, C22:0 and C24:1, for observing their partition and diffusion in SM/cholesterol (chol)/dioleoylphosphatidylcholine (DOPC) bilayers. Although fluorescent C24:1SM underwent a uniform distribution between ordered (Lo) and disordered (Ld) phases, other fluorescent SMs with saturated acyl chains were preferentially distributed in the Lo phase. Interestingly, when the acyl chains of fluorescent and membrane SMs are different, distribution of fluorescent SM to the Lo phase was reduced compared to when the acyl chains are the same. This tendency was also observed for C16:0SM/C22:0SM/chol/DOPC quaternary bilayers, where the minor SM was more excluded out of the Lo phase than the major SM. We also found that the coexistence of SMs induces SM efflux out of the Lo phase and simultaneous DOPC influx to the Lo phase, consequently reducing the difference in fluidity between the two phases. These results suggest that physicochemical properties of lipid rafts are regulated by the acyl chain heterogeneity of SMs.

    DOI: 10.1016/j.bbamem.2022.184036

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  • Formation of a Tight Complex between Amphidinol 3 and Sterols in Lipid Bilayers Revealed by Short-Range Energy Transfer 査読 国際誌

    Hieda, M; Tsujimura, K; Kinoshita, M; Matsumori, N

    BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN   95 ( 12 )   1753 - 1759   2022年11月   ISSN:0009-2673 eISSN:1348-0634

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    記述言語:その他   掲載種別:研究論文(学術雑誌)   出版者・発行元:Bulletin of the Chemical Society of Japan  

    The exploration of molecular recognition in lipid bilayers is still extremely difficult. In this report, we leveraged short-range energy transfer (ET) that enabled detection of close contacts within 1 nm distance, and applied it to the interaction of natural products with sterols in lipid bilayers. Amphidinol 3 (AM3), a polyhydroxypolyene metabolite from a marine dinoflagellate, possesses potent antifungal activity by forming membrane pores in a sterol-dependent manner. Although AM3 was shown to interact directly with membrane sterols, the mode of interaction is yet to be fully elucidated. Herein, we found that AM3 and cholestatrienol (CTL), a fluorescent sterol, can be an ET pair because the emission spectrum of the former overlaps with the excitation of the latter. We further confirmed that CTL exerts the sterol-dependent pore formation of AM3 as in the case of cholesterol. Then, titration using intermolecular ET in bilayers revealed that AM3 and CTL form a 1:1 complex with a dissociation constant of 1.4 © 1015 M. The distance between the AM3 polyene and CTL triene was estimated to be less than 1 nm. Based on this information, we proposed a tight binding model between AM3 and the sterol in lipid bilayers.

    DOI: 10.1246/bcsj.20220273

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  • Behavior of Triterpenoid Saponin Ginsenoside Rh2 in Ordered and Disordered Phases in Model Membranes Consisting of Sphingomyelin, Phosphatidylcholine, and Cholesterol 査読 国際誌

    Garza, DL; Hanashima, S; Umegawa, Y; Murata, M; Kinoshita, M; Matsumori, N; Greimel, P

    LANGMUIR   38 ( 34 )   10478 - 10491   2022年8月   ISSN:0743-7463 eISSN:1520-5827

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    記述言語:その他   掲載種別:研究論文(学術雑誌)   出版者・発行元:Langmuir  

    The ginsenoside Rh2 (Rh2) is a saponin of medicinal ginseng, and it has attracted much attention for its pharmacological activities. In this study, we investigated the interaction of Rh2 with biological membranes using model membranes. We examined the effects of various lipids on the membrane-disrupting activity of Rh2 and found that cholesterol and sphingomyelin (SM) had no significant effect. Furthermore, the effects of Rh2 on acyl chain packing (DPH anisotropy) and water molecule permeability (GP340 values) did not differ significantly between bilayers containing SM and saturated phosphatidylcholine. These results suggest that the formation of the liquid-ordered (Lo) phase affects the behavior of Rh2 in the membrane rather than a specific interaction of Rh2 with a particular lipid. We investigated the effects of Rh2 on the Lo and liquid-disordered (Ld) phases using surface tension measurements and fluorescence experiments. In the surface tension-area isotherms, we compared the monolayers of the Ld and Lo lipid compositions and found that Rh2 is abundantly bound to both monolayers, with the amount being greater in the Ld phase than in the Lo phase. In addition, the hydration state of the bilayers, mainly consisting of the Lo or Ld phase, showed that Rh2 tends to bind to the surface of the bilayer in both phases. At higher concentrations, Rh2 tends to bind more abundantly to the relatively shallow interior of the Ld phase than the Lo phase. The phase-dependent membrane behavior of Rh2 is probably due to the phase-selective affinity and binding mode of Rh2.

    DOI: 10.1021/acs.langmuir.2c01261

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  • Inimitable Impacts of Ceramides on Lipid Rafts Formed in Artificial and Natural Cell Membranes 査読 国際誌

    Kinoshita, M; Matsumori, N

    MEMBRANES   12 ( 8 )   727 - 727   2022年7月   ISSN:2077-0375 eISSN:2077-0375

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    記述言語:その他   掲載種別:研究論文(学術雑誌)   出版者・発行元:Membranes  

    Ceramide is the simplest precursor of sphingolipids and is involved in a variety of biological functions ranging from apoptosis to the immune responses. Although ceramide is a minor constituent of plasma membranes, it drastically increases upon cellular stimulation. However, the mechanistic link between ceramide generation and signal transduction remains unknown. To address this issue, the effect of ceramide on phospholipid membranes has been examined in numerous studies. One of the most remarkable findings of these studies is that ceramide induces the coalescence of membrane domains termed lipid rafts. Thus, it has been hypothesised that ceramide exerts its biological activity through the structural alteration of lipid rafts. In the present article, we first discuss the characteristic hydrogen bond functionality of ceramides. Then, we showed the impact of ceramide on the structures of artificial and cell membranes, including the coalescence of the pre-existing lipid raft into a large patch called a signal platform. Moreover, we proposed a possible structure of the signal platform, in which sphingomyelin/cholesterol-rich and sphingomyelin/ceramide-rich domains coexist. This structure is considered to be beneficial because membrane proteins and their inhibitors are separately compartmentalised in those domains. Considering the fact that ceramide/cholesterol content regulates the miscibility of those two domains in model membranes, the association and dissociation of membrane proteins and their inhibitors might be controlled by the contents of ceramide and cholesterol in the signal platform.

    DOI: 10.3390/membranes12080727

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  • Molecular substructure of the liquid-ordered phase formed by sphingomyelin and cholesterol: sphingomyelin clusters forming nano-subdomains are a characteristic feature 査読 国際誌

    Murata, M; Matsumori, N; Kinoshita, M; London, E

    BIOPHYSICAL REVIEWS   14 ( 3 )   655 - 678   2022年6月   ISSN:1867-2450 eISSN:1867-2469

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    記述言語:その他   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biophysical Reviews  

    As a model of lipid rafts, the liquid-ordered (Lo) phase formed by sphingomyelin (SM) and cholesterol (Cho) in bilayer membranes has long attracted the attention of biophysics researchers. New approaches and methodologies have led to a better understanding of the molecular basis of the Lo domain structure. This review summarizes studies on model membrane systems consisting of SM/unsaturated phospholipid/Cho implying that the Lo phase contains SM-based nanodomains (or nano-subdomains). Some of the Lo phase properties may be attributed to these nanodomains. Several studies suggest that the nanodomains contain clustered SM molecules packed densely to form gel-phase-like subdomains of single-digit nanometer size at physiological temperatures. Cho and unsaturated lipids located in the Lo phase are likely to be concentrated at the boundaries between the subdomains. These subdomains are not readily detected in the Lo phase formed by saturated phosphatidylcholine (PC) molecules, suggesting that they are strongly stabilized by homophilic interactions specific to SM, e.g., between SM amide groups. This model for the Lo phase is supported by experiments using dihydro-SM, which is thought to have stronger homophilic interactions than SM, as well as by studies using the enantiomer of SM having opposite stereochemistry to SM at the 2 and 3 positions and by some molecular dynamics (MD) simulations of lipid bilayers containing Lo-lipids. Nanosized gel subdomains seem to play an important role in controlling membrane organization and function in biological membranes.

    DOI: 10.1007/s12551-022-00967-1

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    その他リンク: https://link.springer.com/article/10.1007/s12551-022-00967-1/fulltext.html

  • Amphotericin B assembles into seven-molecule ion channels: An NMR and molecular dynamics study 査読 国際誌

    Umegawa, Y; Yamamoto, T; Dixit, M; Funahashi, K; Seo, S; Nakagawa, Y; Suzuki, T; Matsuoka, S; Tsuchikawa, H; Hanashima, S; Oishi, T; Matsumori, N; Shinoda, W; Murata, M

    SCIENCE ADVANCES   8 ( 24 )   eabo2658   2022年6月   ISSN:2375-2548

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Science Advances  

    Amphotericin B, an antifungal drug with a long history of use, forms fungicidal ion-permeable channels across cell membranes. Using solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we experimentally elucidated the three-dimensional structure of the molecular assemblies formed by this drug in membranes in the presence of the fungal sterol ergosterol. A stable assembly consisting of seven drug molecules was observed to form an ion conductive channel. The structure is somewhat similar to the upper half of the barrel-stave model proposed in the 1970s but substantially different in the number of molecules and in their arrangement. The present structure explains many previous findings, including structure-activity relationships of the drug, which will be useful for improving drug efficacy and reducing adverse effects.

    DOI: 10.1126/sciadv.abo2658

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  • Binding of cardiolipin to the KcsA channel at the membrane outer leaflet allosterically opens the inner gate

    Masataka Inada, Masayuki Iwamoto, Norio Yoshida, Shigetoshi Oiki, Nobuaki Matsumori

    2022年2月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Cold Spring Harbor Laboratory  

    DOI: 10.1101/2022.02.08.479071

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  • 脂質ラフトを標的とする局所麻酔薬の作用機序

    木下 祥尚, 松森 信明

    Medical Science Digest   48   50 - 51   2022年

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  • Recent advances in microscale separation techniques for lipidome analysis. 招待 査読 国際誌

    Takayuki Kawai, Nobuaki Matsumori, Koji Otsuka

    The Analyst   146 ( 24 )   7418 - 7430   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    This review paper highlights the recent research on liquid-phase microscale separation techniques for lipidome analysis over the last 10 years, mainly focusing on capillary liquid chromatography (LC) and capillary electrophoresis (CE) coupled with mass spectrometry (MS). Lipids are one of the most important classes of biomolecules which are involved in the cell membrane, energy storage, signal transduction, and so on. Since lipids include a variety of hydrophobic compounds including numerous structural isomers, lipidomes are a challenging target in bioanalytical chemistry. MS is the key technology that comprehensively identifies lipids; however, separation techniques like LC and CE are necessary prior to MS detection in order to avoid ionization suppression and resolve structural isomers. Separation techniques using μm-scale columns, such as a fused silica capillary and microfluidic device, are effective at realizing high-resolution separation. Microscale separation usually employs a nL-scale flow, which is also compatible with nanoelectrospray ionization-MS that achieves high sensitivity. Owing to such analytical advantages, microscale separation techniques like capillary/microchip LC and CE have been employed for more than 100 lipidome studies. Such techniques are still being evolved and achieving further higher resolution and wider coverage of lipidomes. Therefore, microscale separation techniques are promising as the fundamental technology in next-generation lipidome analysis.

    DOI: 10.1039/d1an00967b

  • Preparation of Nitrogen Analogues of Ceramide and Studies of Their Aggregation in Sphingomyelin Bilayers. 国際誌

    Hiroki Yasuda, Kohei Torikai, Masanao Kinoshita, Md Abdullah Al Sazzad, Koya Tsujimura, J Peter Slotte, Nobuaki Matsumori

    Langmuir : the ACS journal of surfaces and colloids   37 ( 42 )   12438 - 12446   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ceramides can regulate biological processes probably through the formation of laterally segregated and highly packed ceramide-rich domains in lipid bilayers. In the course of preparation of its analogues, we found that a hydrogen-bond-competent functional group in the C1 position is necessary to form ceramide-rich domains in lipid bilayers [Matsufuji; Langmuir 2018]. Hence, in the present study, we newly synthesized three ceramide analogues: CerN3, CerNH2, and CerNHAc, in which the 1-OH group of ceramide is substituted with a nitrogen functionality. CerNH2 and CerNHAc are capable of forming hydrogen bonds in their headgroups, whereas CerN3 is not. Fluorescent microscopy observation and differential scanning calorimetry analysis disclosed that these ceramide analogues formed ceramide-rich phases in sphingomyelin bilayers, although their thermal stability was slightly inferior to that of normal ceramides. Moreover, wide-angle X-ray diffraction analysis showed that the chain packing structure of ceramide-rich phases of CerNHAc and CerN3 was similar to that of normal ceramide, while the CerNH2-rich phase showed a slightly looser chain packing due to the formation of CerNH3+. Although the domain formation of CerN3 was unexpected because of the lack of hydrogen-bond capability in the headgroup, it may become a promising tool for investigating the mechanistic link between the ceramide-rich phase and the ceramide-related biological functions owing to its Raman activity and applicability to click chemistry.

    DOI: 10.1021/acs.langmuir.1c02101

  • 【再訪:麻酔メカニズム】脂質ラフトと麻酔メカニズム 招待 査読

    松森 信明

    麻酔   70 ( 7 )   724 - 731   2021年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

  • Amphidinol 3 preferentially binds to cholesterol in disordered domains and disrupts membrane phase separation. 国際誌

    Manami Hieda, Akira Sorada, Masanao Kinoshita, Nobuaki Matsumori

    Biochemistry and biophysics reports   26   100941 - 100941   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphidinol 3 (AM3), a polyhydroxy-polyene metabolite from the dinoflagellate Amphidinium klebsii, possesses potent antifungal activity. AM3 is known to interact directly with membrane sterols and permeabilize membranes by forming pores. Because AM3 binds to sterols such as cholesterol and ergosterol, it can be assumed that AM3 has some impact on lipid rafts, which are membrane domains rich in sphingolipids and cholesterol. Hence, we first examined the effect of AM3 on phase-separated liposomes, in which raft-like ordered and non-raft-like disordered domains are segregated. Consequently, AM3 disrupted the phase separation at 22 μM, as in the case of methyl-β-cyclodextrin, a well-known raft-disrupter that extracts sterol from membranes. The surface plasmon resonance measurements and dye leakage assays show that AM3 preferentially recognizes cholesterol in the disordered membrane, which may reflect a weaker lipid-cholesterol interaction in disordered membrane than in ordered membrane. Finally, to gain insight into the AM3-induced coalescence of membrane phases, we measured membrane fluidity using fluorescence correlation spectroscopy, demonstrating that AM3 significantly increases the order of disordered phase. Together, AM3 preferentially binds to the disordered phase rather than the ordered phase, and enhances the order of the disordered phase, consequently blending the separated phases.

    DOI: 10.1016/j.bbrep.2021.100941

  • Metal Complex Lipids for Fluid-Fluid Phase Separation in Coassembled Phospholipid Membranes. 国際誌

    Ryo Ohtani, Yuka Anegawa, Hikaru Watanabe, Yutaro Tajima, Masanao Kinoshita, Nobuaki Matsumori, Kenichi Kawano, Saeko Yanaka, Koichi Kato, Masaaki Nakamura, Masaaki Ohba, Shinya Hayami

    Angewandte Chemie (International ed. in English)   60 ( 24 )   13603 - 13608   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We demonstrate a fluid-fluid phase separation in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) membranes using a metal complex lipid of type [Mn(L1)] (1; HL1=1-(2-hydroxybenzamide)-2-(2-hydroxy-3-formyl-5-hexadecyloxybenzylideneamino)ethane). Small amount of 1 produces two separated domains in DMPC, whose phase transition temperatures of lipids (Tc ) are both lower than that of the pristine DMPC. Variable temperature fluorescent microscopy for giant-unilamellar vesicles of DMPC/1 hybrids demonstrates that visible phase separations remain in fluid phases up to 37 °C, which is clearly over the Tc of DMPC. This provides a new dimension for the application of metal complex lipids toward controlling lipid distributions in fluid membranes.

    DOI: 10.1002/anie.202102774

  • Low-flux scanning electron diffraction reveals substructures inside the ordered membrane domain. 国際誌

    Masanao Kinoshita, Shimpei Yamaguchi, Nobuaki Matsumori

    Scientific reports   10 ( 1 )   22188 - 22188   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ordered/disordered phase separation occurring in bio-membranes has piqued researchers' interest because these ordered domains, called lipid rafts, regulate important biological functions. The structure of the ordered domain has been examined with artificial membranes, which undergo macroscopic ordered/disordered phase separation. However, owing to technical difficulties, the local structure inside ordered domains remains unknown. In this study, we employed electron diffraction to examine the packing structure of the lipid carbon chains in the ordered domain. First, we prepared dehydrated monolayer samples using a rapid-freezing and sublimation protocol, which attenuates the shrinkage of the chain-packing lattice in the dehydration process. Then, we optimised the electron flux to minimise beam damage to the monolayer sample. Finally, we developed low-flux scanning electron diffraction and assessed the chain packing structure inside the ordered domain formed in a distearoylphosphatidylcholine/dioleoylphosphatidylcholine binary monolayer. Consequently, we discovered that the ordered domain contains multiple subdomains with different crystallographic axes. Moreover, the size of the subdomain is larger in the domain centre than that near the phase boundary. To our knowledge, this is the first study to reveal the chain packing structures inside an ordered domain.

    DOI: 10.1038/s41598-020-79083-7

  • Pseudo-Membrane Jackets Two-Dimensional Coordination Polymers Achieving Visible Phase Separation in Cell Membrane 査読

    Ryo Ohtani, Kenichi Kawano, Masanao Kinoshita, Saeko Yanaka, Hikaru Watanabe, Kenji Hirai, Shiroh Futaki, Nobuaki Matsumori, Hiroshi Uji-i, Masaaki Ohba, Koichi Kato, Shinya Hayami

    Angewandte Chemie - International Edition   59 ( 41 )   17931 - 17937   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cell membranes contain lateral systems that consist of various lipid compositions and actin cytoskeleton, providing two-dimensional (2D) platforms for chemical reactions. However, such complex 2D environments have not yet been used as a synthetic platform for artificial 2D nanomaterials. Herein, we demonstrate the direct synthesis of 2D coordination polymers (CPs) at the liquid-cell interface of the plasma membrane of living cells. The coordination-driven self-assembly of networking metal complex lipids produces cyanide-bridged CP layers with metal ions, enabling “pseudo-membrane jackets” that produce long-lived micro-domains with a size of 1–5 μm. The resultant artificial and visible phase separation systems remain stable even in the absence of actin skeletons in cells. Moreover, we show the cell application of the jackets by demonstrating the enhancement of cellular calcium response to ATP.

    DOI: 10.1002/anie.202006600

  • 局所麻酔の新たなメカニズム

    松森 信明

    日本ペインクリニック学会誌   27 ( 3 )   IL1 - IL1   2020年10月

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    記述言語:日本語  

  • Assembly formation of minor dihydrosphingomyelin in sphingomyelin-rich ordered membrane domains. 国際誌

    Masanao Kinoshita, Takumi Kyo, Nobuaki Matsumori

    Scientific reports   10 ( 1 )   11794 - 11794   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The lipidome of mammalian cells not only contain sphingomyelin (SM) but also, as a minor component, dihydrosphongomyelin (DHSM), in which the double bond at C4-C5 in the sphingosine base is reduced to a single-bond linkage. It has been indicated that DHSM forms ordered domains more effectively than SM due to its greater potential to induce intermolecular hydrogen bonds. However, direct information on partition and dynamic behaviors of DHSM in raft-like liquid-ordered (Lo) and non-raft-like liquid-disordered (Ld) phase-segregated membranes has been lacking. In the present study, we prepared fluorescent derivatives of DHSM and compared their behaviors to those of fluorescent SM and phosphatidylcholine (PC) derivatives. Fluorescence microscopy showed that DHSM is more preferentially localized to the Lo domains in the Lo/Ld phase-segregated giant unilamellar vesicles than SM and PC. Most importantly, diffusion coefficient measurements indicated that DHSM molecules form DHSM-condensed assembly inside the SM-rich Lo domain of the SM/dioleoylphosphatidylcholine/cholesterol system even when DHSM accounts for 1-3.3 mol% of total lipids. Such heterogeneous distribution of DHSM in the SM-rich Lo domains was further confirmed by inter-lipid FRET experiments. This study provides new insights into the biological functions and significance of minor component DHSM in lipid rafts.

    DOI: 10.1038/s41598-020-68688-7

  • Chemical diversity and mode of action of natural products targeting lipids in the eukaryotic cell membrane 査読 国際誌

    Shinichi Nishimura, Nobuaki Matsumori

    Natural Product Reports   37 ( 5 )   677 - 702   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Covering: Up to 2019 Nature furnishes bioactive compounds (natural products) with complex chemical structures, yet with simple, sophisticated molecular mechanisms. When natural products exhibit their activities in cells or bodies, they first have to bind or react with a target molecule in/on the cell. The cell membrane is a major target for bioactive compounds. Recently, our understanding of the molecular mechanism of interactions between natural products and membrane lipids progressed with the aid of newly-developed analytical methods. New technology reconnects old compounds with membrane lipids, while new membrane-targeting molecules are being discovered through the screening for antimicrobial potential of natural products. This review article focuses on natural products that bind to eukaryotic membrane lipids, and includes clinically important molecules and key research tools. The chemical diversity of membrane-targeting natural products and the molecular basis of lipid recognition are described. The history of how their mechanism was unveiled, and how these natural products are used in research are also mentioned.

    DOI: 10.1039/c9np00059c

  • Biophysics at Kyushu University. 査読 国際誌

    Ryo Akiyama, Masahiko Annaka, Daisuke Kohda, Hiroyuki Kubota, Yusuke Maeda, Nobuaki Matsumori, Daisuke Mizuno, Norio Yoshida

    Biophysical reviews   12 ( 2 )   245 - 247   2020年4月

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    記述言語:英語  

    DOI: 10.1007/s12551-020-00643-2

  • Total Synthesis of Amphidinol 3: A General Strategy for Synthesizing Amphidinol Analogues and Structure-Activity Relationship Study. 国際誌

    Yuma Wakamiya, Makoto Ebine, Nobuaki Matsumori, Tohru Oishi

    Journal of the American Chemical Society   142 ( 7 )   3472 - 3478   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphidinol 3 (AM3) is a potent antifungal produced by the dinoflagellate Amphidinium klebsii. It was difficult to determine the absolute configuration of AM3 by using the scarce natural product due to the presence of numerous stereogenic centers on the acyclic carbon chain. Since the absolute configuration was partially determined on the basis of insufficient evidence, the originally proposed structure has been revised three times. Although recent progress on structure determination by computational analysis is remarkable, total synthesis is still the most reliable way to confirm structures. The first total synthesis of AM3 was achieved via expeditious assembly of three components in five steps, confirming the revised structure of AM3 after more than 20 years since its first discovery. The established synthetic route would be a general strategy for synthesizing amphidinol congeners. An artificial and simplified analogue of AM3, which elicited antifungal activity comparable to that of AM3, was designed and synthesized. This is the first example of a biologically active artificial analogue possessing a shorter polyol moiety, providing insight on the antifungal mode-of-action.

    DOI: 10.1021/jacs.9b11789

  • The influence of ceramide and its dihydro analog on the physico-chemical properties of sphingomyelin bilayers 査読

    Masanao Kinoshita, Kaoru Tanaka, Nobuaki Matsumori

    Chemistry and Physics of Lipids   226   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The influence of ceramide and its dihydro analog (Cer and DHCer, respectively; inclusively termed Cers) on sphingomyelin (SM) bilayers was examined. Fluorescent microscopy showed that SM/Cers binary bilayers undergo phase separation between Cers-rich and Cers-poor phases. Based on calorimetry, the content of Cers in the Cers-rich phase was estimated and the results show that DHCer in the DHCer-rich phase (17.5 mol%) is more condensed than Cer in the Cer-rich phase (15 mol%), likely due to a stronger intermolecular interaction of DHCer than that of Cer. Furthermore, the Cers-poor phase consists of almost pure SM. X-ray diffraction and water permeability measurements disclosed that the size of crystallites—lipid nano-clusters formed inside the Cers-rich phase—are larger for the DHCer-rich phase than those for the Cer-rich phase. Due to its stronger intermolecular interactions, DHCer could effectively suppress the inter-crystallite packing gaps to avoid the energetic disadvantage, resulting in formation of larger crystallites.

    DOI: 10.1016/j.chemphyslip.2019.104835

  • Archaeal Glycolipid S-TGA-1 Is Crucial for Trimer Formation and Photocycle Activity of Bacteriorhodopsin 査読 国際誌

    Masataka Inada, Masanao Kinoshita, Nobuaki Matsumori

    ACS Chemical Biology   15 ( 1 )   197 - 204   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Copyright © 2019 American Chemical Society. Although it has been demonstrated that membrane proteins (MPs) require lipids to ensure their structural and functional integrity, details on how lipid-MP interactions regulate MPs are still unclear. Recently, we developed a concise method for quantitatively evaluating lipid-MP interactions and applied it to bacteriorhodopsin (bR), a halobacterial MP that forms trimers and acts as a light-driven proton pump. Consequently, we found that the halobacterial glycolipid, S-TGA-1, has the highest affinity for bR, among other lipids. In this study, we examined the effects of S-TGA-1 on bR via visible circular dichroism spectroscopy, flash photolysis, and proton influx measurement. The results showed that S-TGA-1 efficiently promotes trimer formation, photocycle, and proton pumping in bR. Our data also suggested that the bR photocycle is restored as a consequence of the trimerization induced by the lipid. This study demonstrates clearly that lipids specifically interacting with MPs can have significant impacts on MP structure and/or function. The methodology adopted in our studies can be applied to other MPs and will help elucidate the physiological functions of lipids in terms of lipid-MP interactions, thus accelerating "lipid chemical biology" studies.

    DOI: 10.1021/acschembio.9b00756

  • Defining raft domains in the plasma membrane 査読

    Akihiro Kusumi, Takahiro K. Fujiwara, Taka A. Tsunoyama, Rinshi S. Kasai, An An Liu, Koichiro M. Hirosawa, Masanao Kinoshita, Nobuaki Matsumori, Naoko Komura, Hiromune Ando, Kenichi G.N. Suzuki

    Traffic   21 ( 1 )   106 - 137   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Many plasma membrane (PM) functions depend on the cholesterol concentration in the PM in strikingly nonlinear, cooperative ways: fully functional in the presence of physiological cholesterol levels (35~45 mol%), and nonfunctional below 25 mol% cholesterol; namely, still in the presence of high concentrations of cholesterol. This suggests the involvement of cholesterol-based complexes/domains formed cooperatively. In this review, by examining the results obtained by using fluorescent lipid analogs and avoiding the trap of circular logic, often found in the raft literature, we point out the fundamental similarities of liquid-ordered (Lo)-phase domains in giant unilamellar vesicles, Lo-phase-like domains formed at lower temperatures in giant PM vesicles, and detergent-resistant membranes: these domains are formed by cooperative interactions of cholesterol, saturated acyl chains, and unsaturated acyl chains, in the presence of >25 mol% cholesterol. The literature contains evidence, indicating that the domains formed by the same basic cooperative molecular interactions exist and play essential roles in signal transduction in the PM. Therefore, as a working definition, we propose that raft domains in the PM are liquid-like molecular complexes/domains formed by cooperative interactions of cholesterol with saturated acyl chains as well as unsaturated acyl chains, due to saturated acyl chains' weak multiple accommodating interactions with cholesterol and cholesterol's low miscibility with unsaturated acyl chains and TM proteins. Molecules move within raft domains and exchange with those in the bulk PM. We provide a logically established collection of fluorescent lipid probes that preferentially partition into raft and non-raft domains, as defined here, in the PM.

    DOI: 10.1111/tra.12718

  • The Amphotericin B–Ergosterol Complex Spans a Lipid Bilayer as a Single-Length Assembly 査読

    Tomoya Yamamoto, Yuichi Umegawa, Hiroshi Tsuchikawa, Shinya Hanashima, Nobuaki Matsumori, Kosuke Funahashi, Sangjae Seo, Wataru Shinoda, Michio Murata

    Biochemistry   58 ( 51 )   5188 - 5196   2019年12月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1021/acs.biochem.9b00835

  • 天然物のNMR研究―立体化学決定および溶液中と膜中における配座解析

    松森信明

    NMR (Web)   10   76‐81 (WEB ONLY)   2019年11月

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    記述言語:日本語  

    天然物のNMR研究―立体化学決定および溶液中と膜中における配座解析

  • Mechanism of local anesthetic-induced disruption of raft-like ordered membrane domains 査読

    Masanao Kinoshita, Takeshi Chitose, Nobuaki Matsumori

    Biochimica et Biophysica Acta - General Subjects   1863 ( 9 )   1381 - 1389   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Because ordered membrane domains, called lipid rafts, regulate activation of ion channels related to the nerve pulse, lipids rafts are thought to be a possible target for anesthetic molecules. To understand the mechanism of anesthetic action, we examined influence of representative local anesthetics (LAs); dibucaine, tetracaine, and lidocaine, on raft-like liquid-ordered (Lo)/non-raft-like liquid-disordered (Ld) phase separation. Methods: Impact of LAs on the phase separation was observed by fluorescent microscopy. LA-induced perturbation of the Lo and Ld membranes was examined by DPH anisotropy measurements. Incorporation of LAs to the membranes was examined by fluorescent anisotropy of LAs. The biding location of the LAs was indicated by small angle x-ray diffraction (SAXD). Results: Fluorescent experiments showed that dibucaine eliminated the phase separation the most effectively, followed by tetracaine and lidocaine. The disruption of the phase separation can be explained by their disordering effects on the Lo membrane. SAXD and other experiments further suggested that dibucaine's most potent perturbation of the Lo membrane is attributable to its deeper immersion and bulky molecular structure. Tetracaine, albeit immersed in the Lo membrane as deeply as dibucaine, less perturbs the Lo membrane probably because of its smaller bulkiness. Lidocaine hardly reaches the hydrophobic region, resulting in the weakest Lo membrane perturbation. Conclusion: Dibcaine perturbs the Lo membrane the most effectively, followed by tetracaine and lidocaine. This ranking correlates with their anesthetic potency. General significance: This study suggests a possible mechanistic link between anesthetic action and perturbation of lipid rafts.

    DOI: 10.1016/j.bbagen.2019.06.008

  • Cholesterol-Induced Conformational Change in the Sphingomyelin Headgroup 査読

    Shinya Hanashima, Kazuhiro Murakami, Michihiro Yura, Yo Yano, Yuichi Umegawa, Hiroshi Tsuchikawa, Nobuaki Matsumori, Sangjae Seo, Wataru Shinoda, Michio Murata

    Biophysical Journal   117 ( 2 )   307 - 318   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sphingomyelin (SM) and cholesterol (Cho) are the important lipids for the formation of biologically functional membrane domains, lipid rafts. However, the interaction between Cho and the headgroup of SM remains unclear. In this study, we performed solid-state NMR experiments to reveal the Cho effects on the headgroup conformation using 2H-labeled stearoyl-SM (SSM). Deuterated SSMs at the Cα, Cβ, and Cγ positions of a choline moiety were separately prepared and subjected to NMR measurements to determine the quadrupolar splitting of 2H signals in hydrated SSM unitary and SSM/Cho (1:1) bilayers. Using 2H NMR and 13C-31P REDOR data, the conformation and orientation of the choline moiety were deduced and compared with those derived from molecular dynamics simulations. In SSM unitary bilayers, three torsional angles in the phosphocholine moiety, P-O-Cα-Cβ, were found to be consecutive +gauche(g)/+g/+g or −g/−g/−g. The orientation and conformation of the SSM headgroup were consistent with the results of our molecular dynamics simulations and the previous results on phosphatidylcholines. The quadrupolar coupling at the α methylene group slightly increased in the presence of Cho, and those at the Cβ and Cγ decreased more significantly, thus suggesting that Cho reduced the gauche conformation at the Cα-Cβ torsion. The conformational ensemble in the presence of Cho may enhance the so-called umbrella effect of the SSM headgroup, resulting in the stabilization of Cho near the SM molecules by concealing the hydrophobic Cho core from interfacial water. We also examined the effect of the chiral centers at the sphingosine chain to the headgroup conformation by determining the enantiomeric excess between the diastereomeric +g/+g/+g and −g/−g/−g conformers using (S)-Cα-deuterated and (R)-Cα-deuterated SSMs. Their 2H NMR measurements showed that the chiral centers induced the slight diastereomeric excess in the SM headgroup conformation.

    DOI: 10.1016/j.bpj.2019.06.019

  • A concise method for quantitative analysis of interactions between lipids and membrane proteins. 査読 国際誌

    Masataka Inada, Masanao Kinoshita, Ayumi Sumino, Shigetoshi Oiki, Nobuaki Matsumori

    Analytica chimica acta   1059   103 - 112   2019年6月

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    記述言語:英語  

    Although interactions between lipids and membrane proteins (MPs) have been considered crucially important for understanding the functions of lipids, lack of useful and convincing experimental methods has hampered the analysis of the interactions. Here, we developed a surface plasmon resonance (SPR)-based concise method for quantitative analysis of lipid-MP interactions, coating the sensor chip surface with self-assembled monolayer (SAM) with C6-chain. To develop this method, we used bacteriorhodopsin (bR) as an MP, and examined its interaction with various types of lipids. The merits of using C6-SAM-modified sensor chip are as follows: (1) alkyl-chains of SAM confer a better immobilization of MPs because of the efficient preconcentration due to hydrophobic contacts; (2) SAM provides immobilized MPs with a partial membranous environment, which is important for the stabilization of MPs; and (3) a thinner C6-SAM layer (1 nm) compared with MP size forces the MP to bulge outward from the SAM surface, allowing extraneously injected lipids to be accessible to the hydrophobic transmembrane regions. Actually, the amount of bR immobilized on C6-SAM is 10 times higher than that on a hydrophilic CM5 sensor chip, and AFM observations confirmed that bR molecules are exposed on the SAM surface. Of the lipids tested, S-TGA-1, a halobacterium-derived glycolipid, had the highest specificity to bR with a nanomolar dissociation constant. This is consistent with the reported co-crystal structure that indicates the formation of several intermolecular hydrogen bonds. Therefore, we not only reproduced the specific lipid-bR recognition, but also succeeded in its quantitative evaluation, demonstrating the validity and utility of this method.

    DOI: 10.1016/j.aca.2019.01.042

  • The Perpendicular Orientation of Amphotericin B Methyl Ester in Hydrated Lipid Bilayers Supports the Barrel-Stave Model 査読

    Tomoya Yamamoto, Yuichi Umegawa, Masaki Yamagami, Taiga Suzuki, Hiroshi Tsuchikawa, Shinya Hanashima, Nobuaki Matsumori, Michio Murata

    Biochemistry   58 ( 17 )   2282 - 2291   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The clinically important antibiotic amphotericin B (AmB) is a membrane-active natural product that targets membrane sterol. The antimicrobial activity of AmB is generally attributed to its membrane permeabilization, which occurs when a pore is formed across a lipid bilayer. In this study, the molecular orientation of AmB was investigated using solid-state nuclear magnetic resonance (NMR) to better understand the mechanism of antifungal activity. The methyl ester of AmB (AME) labeled with NMR isotopes, d3-AME, and its fluorinated and/or 13C-labeled derivatives were prepared. All of the AmB derivatives showed similar membrane-disrupting activities and ultraviolet spectra in phospholipid liposomes, suggesting that their molecular assemblies in membranes closely mimic those of AmB. Solid-state 2H NMR measurements of d3-AME in a hydrated membrane showed that the mobility of AME molecules depends on concentration and temperature. At a 1:5:45 AME:Erg:dimyristoylphosphatidylcholine ratio, AME became sufficiently mobilized to observe the motional averaging of quadrupole coupling. On the basis of the rotational averaging effect of 19F chemical shift anisotropy, 2H quadrupolar splitting, and 13C-19F dipolar coupling of 14β-F-AMEs, we deduced that the molecular axis of AME is predominantly parallel to the normal of a lipid bilayer. This result supports the barrel-stave model as a molecular assembly of AmB in membranes. ©

    DOI: 10.1021/acs.biochem.9b00180

  • Preparation and Membrane Distribution of Fluorescent Derivatives of Ceramide 査読

    Takaaki Matsufuji, Masanao Kinoshita, Nobuaki Matsumori

    Langmuir   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ceramide is a bioactive lipid with significant roles in several biological processes including cell proliferation, apoptosis, and raft formation. Although fluorescent derivatives of ceramide are required to probe the behavior of ceramide in cells and cell membranes, commercial fluorescent ceramide derivatives do not reproduce the membrane behavior of native ceramide because of the introduction of bulky fluorophores in the acyl chain. Recently, we developed novel fluorescent analogs of sphingomyelin in which the hydrophilic fluorophores, ATTO488 and ATTO594, are attached to the polar head of sphingomyelin via a nonaethylene glycol linker and demonstrated that their partition and dynamic behaviors in bilayer membranes are similar to native sphingomyelin. In this report, by extending the concept used for the development of fluorescent analogs of sphingomyelin, we prepared novel fluorescent ceramides that exhibit membrane behaviors similar to native ceramide and succeeded in visualizing ceramide-rich membrane domains segregated from ceramide-poor domains.

    DOI: 10.1021/acs.langmuir.8b03176

  • On the Importance of the C(1)-OH and C(3)-OH Functional Groups of the Long-Chain Base of Ceramide for Interlipid Interaction and Lateral Segregation into Ceramide-Rich Domains 査読

    Anna Möuts, Elina Vattulainen, Takaaki Matsufuji, Masanao Kinoshita, Nobuaki Matsumori, J. Peter Slotte

    Langmuir   34 ( 51 )   15864 - 15870   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ceramides are important intermediates in sphingolipid biosynthesis (and degradation) and are normally present in only small amounts in unstressed cells. However, following the receptor-mediated activation of neutral sphingomyelinase, sphingomyelin can acutely give rise to substantial amounts of ceramides, which dramatically alter membrane properties. In this study, we have examined the role of the 1-OH and 3-OH functional groups of ceramide for its membrane properties. We have specifically examined how the oxidation of the primary alcohol to COOH or COOMe in palmitoyl ceramide (PCer) or the removal of either the primary alcohol or C(3)-OH (deoxy analogs) affected ceramides' interlipid interactions in fluid phosphatidylcholine bilayers. Measuring the time-resolved fluorescence emission of trans-parinaric acid, or its steady-state anisotropy, we have obtained information about the propensity of the ceramide analogs to form ceramide-rich domains and the thermostability of the formed domains. We observed that the oxidation of the primary alcohol to COOH shifted the ceramide's gel-phase onset concentration to slightly higher values in 1-palmitoyl-2-oleoyl-sn-3-glycero-3-phosphocholine (POPC) bilayers. Methylation of the COOH function of the ceramide did not change the segregation tendency further. The complete removal of the primary alcohol dramatically reduced the ability of 1-deoxy-PCer to form ceramide-rich ordered domains. However, the removal 3-OH (in 3-deoxy-PCer) had only small effects on the lateral segregation of the ceramide analog. The thermostability of the ceramide-rich domains in the POPC bilayers decreased in the following order: 1-OH > COOH > COOMe = 3-deoxy > 1-deoxy. We conclude that ceramide needs a hydrogen-bonding-competent functional group in the C(1) position to be able to form laterally segregated ceramide-rich domains of high packing density in POPC bilayers. The presence or absence of 3-OH was not functionally critical for ceramide's lateral segregation properties.

    DOI: 10.1021/acs.langmuir.8b03237

  • 蛍光修飾したスフィンゴミエリン誘導体の脂質ラフト観察への応用

    木下 祥尚, 松森 信明

    生物物理   58 ( 6 )   321 - 323   2018年11月

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    記述言語:日本語  

    Excellent Fluorescent Sphingomyelin Analog Reveals the Existence of Lipid Rafts

  • Sphingomyelin Stereoisomers Reveal That Homophilic Interactions Cause Nanodomain Formation 査読

    Yo Yano, Shinya Hanashima, Tomokazu Yasuda, Hiroshi Tsuchikawa, Nobuaki Matsumori, Masanao Kinoshita, Md Abdullah Al Sazzad, J. Peter Slotte, Michio Murata

    Biophysical Journal   115 ( 8 )   1530 - 1540   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sphingomyelin is an abundant lipid in some cellular membrane domains, such as lipid rafts. Hydrogen bonding and hydrophobic interactions of the lipid with surrounding components such as neighboring sphingomyelin and cholesterol (Cho) are widely considered to stabilize the raft-like liquid-ordered (Lo) domains in membrane bilayers. However, details of their interactions responsible for the formation of Lo domains remain largely unknown. In this study, the enantiomer of stearoyl sphingomyelin (ent-SSM) was prepared, and its physicochemical properties were compared with the natural SSM and the diastereomer of SSM to examine possible stereoselective lipid-lipid interactions. Interestingly, differential scanning calorimetry experiments demonstrated that palmitoyl sphingomyelin, with natural stereochemistry, exhibited higher miscibility with SSM bilayers than with ent-SSM bilayers, indicating that the homophilic sphingomyelin interactions occurred in a stereoselective manner. Solid-state 2H NMR revealed that Cho elicited its ordering effect very similarly on SSM and ent-SSM (and even on the diastereomer of SSM), suggesting that SSM-Cho interactions are not significantly affected by stereospecific hydrogen bonding. SSM and ent-SSM formed gel-like domains with very similar lateral packing in SSM/Cho/palmitoyloleoyl phosphatidylcholine membranes, as shown by fluorescence lifetime experiments. This observation can be explained by a homophilic hydrogen-bond network, which was largely responsible for the formation of gel-like nanodomains of SSMs (or ent-SSM). Our previous study revealed that Cho-poor gel-like domains contributed significantly to the formation of an Lo phase in sphingomyelin/Cho membranes. The results of the study presented here further show that SSM-SSM interactions occur near the headgroup region, whereas hydrophobic SSM-Cho interactions appeared important in the bilayer interior for Lo domain formation. The homophilic interactions of sphingomyelins could be mainly responsible for the formation of the domains of nanometer size, which may correspond to the small sphingomyelin/Cho-based rafts that temporally occur in biological membranes.

    DOI: 10.1016/j.bpj.2018.08.042

  • Evidence of lipid rafts based on the partition and dynamic behavior of sphingomyelins 査読

    Masanao Kinoshita, Kenichi G.N. Suzuki, Michio Murata, Nobuaki Matsumori

    Chemistry and Physics of Lipids   215   84 - 95   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sphingomyelin (SM)-rich membrane nano-domains, called lipid rafts, have attracted the interest of researchers due to their potential involvement in the formation of signaling platform. Although there are many studies on lipid rafts, the direct observation of lipid rafts is still challenging owing to two critical reasons. One is the lack of an appropriate fluorescent probe mimicking the native behavior of raft lipids; fluorescent labeling often alters the intrinsic disposition of raft lipids. The other is their spatio-temporal stability; the size of lipid rafts is much smaller than the optical resolution of usual microscopy and their lifetime is much shorter than image acquisition duration. These issues are hampering the visualization of lipid rafts. Our review highlights the recent advances in microscopic techniques to visualize the partition and dynamic behavior of SMs, disclosing the detailed structure of lipid rafts. Moreover, we will elucidate the importance of SM-SM interactions in the stabilization of signaling platforms as lipid rafts.

    DOI: 10.1016/j.chemphyslip.2018.07.002

  • 生体膜を標的にする天然有機化合物 天然物による厳密な脂質認識とそれに基づく表現型

    西村 慎一, 掛谷 秀昭, 松森 信明

    化学と生物   56 ( 10 )   678 - 684   2018年9月

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    記述言語:日本語  

    生体膜を標的にする天然有機化合物 天然物による厳密な脂質認識とそれに基づく表現型

  • Theonellamide A, a marine-sponge-derived bicyclic peptide, binds to cholesterol in aqueous DMSO: Solution NMR-based analysis of peptide-sterol interactions using hydroxylated sterol. 査読

    Cornelio K, Espiritu RA, Hanashima S, Todokoro Y, Malabed R, Kinoshita M, Matsumori N, Murata M, Nishimura S, Kakeya H, Yoshida M, Matsunaga S

    Biochimica et biophysica acta. Biomembranes   1861 ( 1 )   228 - 235   2018年7月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Theonellamide A, a marine-sponge-derived bicyclic peptide, binds to cholesterol in aqueous DMSO: Solution NMR-based analysis of peptide-sterol interactions using hydroxylated sterol.

    DOI: 10.1016/j.bbamem.2018.07.010

  • Synthesis and Stereochemical Revision of the C31–C67 Fragment of Amphidinol 3 査読

    Yuma Wakamiya, Makoto Ebine, Mariko Murayama, Hiroyuki Omizu, Nobuaki Matsumori, Michio Murata, Tohru Oishi

    Angewandte Chemie - International Edition   57 ( 21 )   6060 - 6064   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphidinol 3 (AM3) is a marine natural product produced by the dinoflagellate Amphidinium klebsii. Although the absolute configuration of AM3 was determined in 1999 by extensive NMR analysis and degradation of the natural product, it was a daunting task because of the presence of numerous stereogenic centers on the acyclic carbon chain and the limited availability from natural sources. Thereafter, revisions of the absolute configurations at C2 and C51 were reported in 2008 and 2013, respectively. Reported herein is the revised absolute configuration of AM3: 32S, 33R, 34S, 35S, 36S, and 38S based on the chemical synthesis of partial structures corresponding to the C31–C67 fragment of AM3 in combination with degradation of the natural product. The revised structure is unique in that both antipodal tetrahydropyran counterparts exist on a single carbon chain. The structural revision of AM3 may affect proposed structures of congeners related to the amphidinols.

    DOI: 10.1002/anie.201712167

  • Synthesis and Stereochemical Revision of the C31-C67 Fragment of Amphidinol 3 査読

    Yuma Wakamiya, Makoto Ebine, Mariko Murayama, Hiroyuki Omizu, Nobuaki Matsumori, Michio Murata, Tohru Oishi

    Angewandte Chemie   130 ( 21 )   6168   2018年5月

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    記述言語:その他  

    Synthesis and Stereochemical Revision of the C31-C67 Fragment of Amphidinol 3

    DOI: 10.1002/ange.201712167

  • Synthesis and complete structure determination of a sperm-activating and -attracting factor isolated from the ascidian ascidia sydneiensis 査読

    Tomohiro Watanabe, Hajime Shibata, Makoto Ebine, Hiroshi Tsuchikawa, Nobuaki Matsumori, Michio Murata, Manabu Yoshida, Masaaki Morisawa, Shu Lin, Kosei Yamauchi, Ken Sakai, Tohru Oishi

    Journal of Natural Products   81 ( 4 )   985 - 997   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    For the complete structure elucidation of an endogenous sperm-activating and -attracting factor isolated from eggs of the ascidian Ascidia sydneiensis (Assydn-SAAF), its two possible diastereomers with respect to C-25 were synthesized. Starting from ergosterol, the characteristic steroid backbone was constructed by using an intramolecular pinacol coupling reaction and stereoselective reduction of a hydroxy ketone as key steps, and the side chain was introduced by Julia-Kocienski olefination. Comparison of the NMR data of the two diastereomers with those of the natural product led to the elucidation of the absolute configuration as 25S; thus the complete structure was determined and the first synthesis of Assydn-SAAF was achieved.

    DOI: 10.1021/acs.jnatprod.7b01052

  • Dynamic membrane interactions of antibacterial and antifungal biomolecules, and amyloid peptides, revealed by solid-state NMR spectroscopy 査読

    Akira Naito, Nobuaki Matsumori, Ayyalusamy Ramamoorthy

    Biochimica et Biophysica Acta - General Subjects   1862 ( 2 )   307 - 323   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A variety of biomolecules acting on the cell membrane folds into a biologically active structure in the membrane environment. It is, therefore, important to determine the structures and dynamics of such biomolecules in a membrane environment. While several biophysical techniques are used to obtain low-resolution information, solid-state NMR spectroscopy is one of the most powerful means for determining the structure and dynamics of membrane bound biomolecules such as antibacterial biomolecules and amyloidogenic proteins; unlike X-ray crystallography and solution NMR spectroscopy, applications of solid-state NMR spectroscopy are not limited by non-crystalline, non-soluble nature or molecular size of membrane-associated biomolecules. This review article focuses on the applications of solid-state NMR techniques to study a few selected antibacterial and amyloid peptides. Solid-state NMR studies revealing the membrane inserted bent α-helical structure associated with the hemolytic activity of bee venom melittin and the chemical shift oscillation analysis used to determine the transmembrane structure (with α-helix and 310-helix in the N- and C-termini, respectively) of antibiotic peptide alamethicin are discussed in detail. Oligomerization of an amyloidogenic islet amyloid polypeptide (IAPP, or also known as amylin) resulting from its aggregation in a membrane environment, molecular interactions of the antifungal natural product amphotericin B with ergosterol in lipid bilayers, and the mechanism of lipid raft formation by sphingomyelin studied using solid state NMR methods are also discussed in this review article. This article is part of a Special Issue entitled “Biophysical Exploration of Dynamical Ordering of Biomolecular Systems” edited by Dr. Koichi Kato.

    DOI: 10.1016/j.bbagen.2017.06.004

  • Preparation and Membrane Properties of Oxidized Ceramide Derivatives 査読

    Takaaki Matsufuji, Masanao Kinoshita, Anna Möuts, J. Peter Slotte, Nobuaki Matsumori

    Langmuir   34 ( 1 )   465 - 471   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ceramide is a bioactive lipid with important roles in several biological processes including cell proliferation and apoptosis. Although 3-ketoceramides that contain a keto group in place of the 3-OH group of ceramide occur naturally, ceramide derivatives oxidized at the primary 1-OH group have not been identified to date. To evaluate how the oxidative state of the 1-OH group affects the physical properties of membranes, we prepared novel ceramide derivatives in which the 1-OH group was oxidized to a carboxylic acid (PCerCOOH) or methylester (PCerCOOMe) and examined the rigidity of their monolayers and the formation of gel domains in palmitoyloleoylphosphatidylcholine (POPC) or sphingomyelin (SM) bilayers. As a result, PCerCOOH and PCerCOOMe exhibited membrane properties similar to those of native ceramide, although the deprotonated form of PCerCOOH, PCerCOO-, exhibited markedly lower rigidity and higher miscibility with POPC and SM. This was attributed to the electrostatic repulsion of the negative charge, which hampered the formation of the ceramide-enriched gel domain. The similarities in the properties of PCerCOOMe and ceramide revealed the potential to introduce various functional groups onto PCerCOOH via ester or amide linkages; therefore, these derivatives will also provide a new strategy for developing molecular probes, such as fluorescent ceramides, and inhibitors of ceramide-related enzymes.

    DOI: 10.1021/acs.langmuir.7b02654

  • Recent Solid-State NMR Studies of Hydrated Lipid Membranes 査読

    Yuichi Umegawa, Nobuaki Matsumori, Michio Murata

    Annual Reports on NMR Spectroscopy   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Interactional and structural analyses of lipids in hydrated biomembranes are at the frontier of membrane physics and biology. Recently, solid-state NMR has emerged as a frequently used technique for the investigation of biomembrane systems, leading to particularly remarkable advances in the study of the structural biology of membrane proteins. However, conformational and interactional analyses of lipid molecules and membrane-active small compounds remain challenging. This chapter highlights recent applications of solid-state NMR to membrane lipids and nonpeptidic molecules such as membrane-active natural products. Lipid rafts are microdomains in cellular membranes formed by sphingomyelin and cholesterol and are thought to constitute a platform for signal transduction. Amphotericin B, theonellamide-A, and amphidinol 3 exert their activities by interacting with lipid membranes. Deuterium quadrupole coupling combined with dipole-dipole interactions has been used to evaluate the interaction modes and dynamic properties of membrane lipids and small membrane-active compounds. Herein, we review the recent advances in these topics using our recent research studies as examples of solid-state NMR investigations of hydrated lipid bilayers.

    DOI: 10.1016/bs.arnmr.2017.12.003

  • Channel Formation and Membrane Deformation via Sterol-Aided Polymorphism of Amphidinol 査読

    Masayuki Iwamoto, Ayumi Sumino, Eri Shimada, Masanao Kinoshita, Nobuaki Matsumori, Shigetoshi Oiki

    Scientific Reports   7 ( 1 )   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphidinol 3 (AM3) is an anti-fungal polyene extracted from a marine dinoflagellate. Here, we examined the ion channel activity and membrane-embedded structure of AM3 using a lipid bilayer method and atomic force microscopy (AFM). AM3 exhibited large-conductance (∼1 nS) and non-selective single-channel activity only when sterols were present in the membrane leaflet of the AM3-added side. The variable conductance suggests the formation of a multimeric barrel-stave pore. At high AM3 concentrations, giant-conductance "jumbo" channels (∼40 nS) emerged. AFM revealed a thicker raft-like membrane phase with the appearance of a wrinkled surface, in which phase pores (diameter: ∼10 nm) were observed. The flip-flop of ergosterol occurred only after the appearance of the jumbo channel, indicating that the jumbo channel induced a continuity between the outer and inner leaflets of the membrane: a feature characteristic of toroidal-like pores. Thus, AM3 forms different types of sterol-aided polymorphic channels in a concentration dependent manner.

    DOI: 10.1038/s41598-017-11135-x

  • The impact of metal complex lipids on viscosity and curvature of hybrid liposomes 査読 国際誌

    Ryo Ohtani, Tsukasa Tokita, Tomohisa Takaya, Koichi Iwata, Masanao Kinoshita, Nobuaki Matsumori, Masaaki Nakamura, Leonard F. Lindoy, Shinya Hayami

    Chemical Communications   53 ( 99 )   13249 - 13252   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A morphology transformation of hybrid liposomes was shown to occur from spherical vesicles to tubular micelles when increasing the ratio of the metal complex lipid present. Phase transition temperatures increased while viscosities decreased, indicating that the hybrids exhibit stronger interaction between heads but weaker interaction between alkyl chains than occurs in pristine liposomes.

    DOI: 10.1039/c7cc07944c

  • Emphatic visualization of sphingomyelin-rich domains by inter-lipid FRET imaging using fluorescent sphingomyelins 査読

    Masanao Kinoshita, Hikaru Ano, Michio Murata, Kenta Shigetomi, Junichi Ikenouchi, Nobuaki Matsumori

    Scientific Reports   7 ( 1 )   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Imaging the distribution of sphingomyelin (SM) in membranes is an important issue in lipid-raft research. Recently we developed novel fluorescent SM analogs that exhibit partition and dynamic behaviors similar to native SM, and succeeded in visualizing lateral domain-segregation between SM-rich liquid-ordered (Lo) and SM-poor liquid-disordered (Ld) domains. However, because the fluorescent contrast between these two domains depends directly on their partition ratio for the fluorescent SMs, domain-separation becomes indeterminate when the distribution difference is not great enough. In this study, we propose the use of inter-lipid Förster resonance energy transfer (FRET) imaging between fluorescent SMs to enhance the contrast of the two domains in cases in which the inter-domain difference in SM distribution is inadequate for conventional monochromic imaging. Our results demonstrate that inter-lipid FRET intensity was significantly higher in the Lo domain than in the Ld domain, resulting in a clear and distinguishable contrast between the two domains even in poorly phase-separated giant unilamellar vesicles. In addition, we show that inter-lipid FRET imaging is useful for selective visualization of highly condensed assemblies and/or clusters of SM molecules in living cell membranes. Thus, the inter-lipid FRET imaging technique can selectively emphasize the SM-condensed domains in both artificial and biological membranes.

    DOI: 10.1038/s41598-017-16361-x

  • Structures of the Largest Amphidinol Homologues from the Dinoflagellate Amphidinium carterae and Structure-Activity Relationships 査読

    Masayuki Satake, Kimberly Cornelio, Shinya Hanashima, Raymond Malabed, Michio Murata, Nobuaki Matsumori, Huiping Zhang, Fumiaki Hayashi, Shoko Mori, Jong Souk Kim, Chang Hoon Kim, Jong Soo Lee

    Journal of Natural Products   80 ( 11 )   2883 - 2888   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphidinols are polyketide metabolites produced by marine dinoflagellates and are chiefly composed of a long linear chain with polyol groups and polyolefins. Two new homologues, amphidinols 20 (AM20, 1) and 21 (AM21, 2), were isolated from Amphidinium carterae collected in Korea. Their structures were elucidated by detailed NMR analyses as amphidinol 6-type compounds with remarkably long polyol chains. Amphidinol 21 (2) has the longest linear structure among the amphidinol homologues reported so far. The congeners, particularly amphidinol 21 (2), showed weaker activity in hemolysis and antifungal assays compared to known amphidinols.

    DOI: 10.1021/acs.jnatprod.7b00345

  • NMR studies on natural product-stereochemical determination and conformational analysis in solution and in membrane

    Nobuaki Matsumori, Michio Murata

    Experimental Approaches of NMR Spectroscopy Methodology and Application to Life Science and Materials Science   383 - 414   2017年11月

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    記述言語:英語  

    In this chapter we overview two topics on NMR methodologies for small molecules, mostly natural products; one is about the solution NMR-based methods used for stereochemical determination of natural products, and the other is on the solid-state and other techniques for investigating natural product-membrane interactions. Since important two methods for stereochemical analysis of natural products, namely the J-based configuration analysis (JBCA) and universal NMR database (UDB) methods, were reported in the 1990s, both methods have been widely used in the field of natural products. The newly coming RDC method is not the major method in the field of natural products yet, but will surely be an important tool for the stereochemical correlation between distant stereogenic centers, which could provide invaluable information as to the whole shape of natural products in solution. In the latter part of this chapter, we discuss the application of solid-state and other NMR techniques to membrane interaction analysis of natural products. In particular, we describe three examples of natural products that interact with biological membranes such as amphotericin B, erythromycin A, and theonellamide A. As shown in NMR studies of amphotericin B, natural products often reveal very high affinities for phospholipids and sterols in bilayer membranes. Solid-state NMR, therefore, provides a very promising approach toward the structure study of membrane-active complexes formed by natural products that have high affinity to lipids. In addition, solution NMR techniques can be applied to elucidate the structural features of membrane-bound small molecules such as antibiotic erythromycin A and membrane-disrupting cyclic peptide theonellamide A. Standard 2D 1H-1H experiments such as COSY (correlation spectroscopy), NOESY (nuclear Overhauser effect spectroscopy), and DOSY (diffusion-ordered spectroscopy) are often helpful in elucidating the membrane interaction between natural products and lipids.

    DOI: 10.1007/978-981-10-5966-7_14

  • Membrane protein structure determination by SAD, SIR, or SIRAS phasing in serial femtosecond crystallography using an iododetergent 査読

    Takanori Nakane, Shinya Hanashima, Mamoru Suzuki, Haruka Saiki, Taichi Hayashi, Keisuke Kakinouchi, Shigeru Sugiyama, Satoshi Kawatake, Shigeru Matsuoka, Nobuaki Matsumori, Eriko Nango, Jun Kobayashi, Tatsuro Shimamura, Kanako Kimura, Chihiro Mori, Naoki Kunishima, Michihiro Sugahara, Yoko Takakyu, Shigeyuki Inoue, Tetsuya Masuda, Toshiaki Hosaka, Kensuke Tono, Yasumasa Joti, Takashi Kameshima, Takaki Hatsui, Makina Yabashi, Tsuyoshi Inoue, Osamu Nureki, So Iwata, Michio Murata, Eiichi Mizohata

    Proceedings of the National Academy of Sciences of the United States of America   113 ( 46 )   13039 - 13044   2016年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The 3D structure determination of biological macromolecules by X-ray crystallography suffers from a phase problem: to perform Fourier transformation to calculate real space density maps, both intensities and phases of structure factors are necessary; however, measured diffraction patterns give only intensities. Although serial femtosecond crystallography (SFX) using X-ray free electron lasers (XFELs) has been steadily developed since 2009, experimental phasing still remains challenging. Here, using 7.0-keV (1.771 Å) X-ray pulses from the SPring-8 Angstrom Compact Free Electron Laser (SACLA), iodine single-wavelength anomalous diffraction (SAD), single isomorphous replacement (SIR), and single isomorphous replacement with anomalous scattering (SIRAS) phasing were performed in an SFX regime for a model membrane protein bacteriorhodopsin (bR). The crystals grown in bicelles were derivatized with an iodine-labeled detergent heavy-atom additive 13a (HAD13a), which contains the magic triangle, I3C head group with three iodine atoms. The alkyl tail was essential for binding of the detergent to the surface of bR. Strong anomalous and isomorphous difference signals from HAD13a enabled successful phasing using reflections up to 2.1-Å resolution from only 3,000 and 4,000 indexed images from native and derivative crystals, respectively. When more images were merged, structure solution was possible with data truncated at 3.3-Å resolution, which is the lowest resolution among the reported cases of SFX phasing. Moreover, preliminary SFX experiment showed that HAD13a successfully derivatized the G protein-coupled A2a adenosine receptor crystallized in lipidic cubic phases. These results pave the way for de novo structure determination of membrane proteins, which often diffract poorly, even with the brightest XFEL beams.

    DOI: 10.1073/pnas.1602531113

  • The Structure of the Bimolecular Complex between Amphotericin B and Ergosterol in Membranes Is Stabilized by Face-to-Face van der Waals Interaction with Their Rigid Cyclic Cores 査読

    Yasuo Nakagawa, Yuichi Umegawa, Naohiro Matsushita, Tomoya Yamamoto, Hiroshi Tsuchikawa, Shinya Hanashima, Tohru Oishi, Nobuaki Matsumori, Michio Murata

    Biochemistry   55 ( 24 )   3392 - 3402   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B (AmB) is a polyene macrolide antibiotic isolated from Streptomyces nodosus. The antifungal activity of AmB can be attributed to the formation of an ion-channel assembly in the presence of ergosterol (Erg), in which there are two different AmB-Erg orientations, parallel and antiparallel, as reported previously. In this study, to elucidate the structures of those AmB-Erg complexes based on solid-state nuclear magnetic resonance, a 19F-labeled AmB derivative was newly prepared by a hybrid synthesis that utilized degradation products from the drug. Using the 2-(trimethylsilyl)ethoxymethyl (SEM) group as the protecting group for the carboxylic acid moiety of AmB, the fully deprotected labeled AmB compounds were obtained successfully. Then, these labeled AmBs were subjected to 13C{19F} rotational-echo double-resonance (REDOR) experiments in hydrated lipid bilayers. The results indicated the coexistence of parallel and antiparallel orientations for AmB and Erg pairing, at a ratio of 7:3. A total of six distances between AmB and Erg were successfully obtained. Geometry analysis using the distance constraints derived from the REDOR experiments provided the plausible AmB-Erg complex structure for both the parallel and antiparallel interactions. The flat macrolide of AmB and the tetracyclic core of Erg closely contacted in a face-to-face manner, thus maximizing the van der Waals interaction between the two molecules. This interaction can be attributed to the coexistence of both the parallel and antiparallel orientations.

    DOI: 10.1021/acs.biochem.6b00193

  • Marine sponge cyclic peptide theonellamide A disrupts lipid bilayer integrity without forming distinct membrane pores 査読

    Rafael Atillo Espiritu, Kimberly Cornelio, Masanao Kinoshita, Nobuaki Matsumori, Michio Murata, Shinichi Nishimura, Hideaki Kakeya, Minoru Yoshida, Shigeki Matsunaga

    Biochimica et Biophysica Acta - Biomembranes   1858 ( 6 )   1373 - 1379   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Theonellamides (TNMs) are antifungal and cytotoxic bicyclic dodecapeptides derived from the marine sponge Theonella sp. These peptides specifically bind to 3β-hydroxysterols, resulting in 1,3-β-d-glucan overproduction and membrane damage in yeasts. The inclusion of cholesterol or ergosterol in phosphatidylcholine membranes significantly enhanced the membrane affinity of theonellamide A (TNM-A) because of its direct interaction with 3β-hydroxyl groups of sterols. To better understand TNM-induced membrane alterations, we investigated the effects of TNM-A on liposome morphology. 31P nuclear magnetic resonance (NMR) and dynamic light scattering (DLS) measurements revealed that the premixing of TNM-A with lipids induced smaller vesicle formation. When giant unilamellar vesicles were incubated with exogenously added TNM-A, confocal micrographs showed dynamic changes in membrane morphology, which were more frequently observed in cholesterol-containing than sterol-free liposomes. In conjunction with our previous data, these results suggest that the membrane action of TNM-A proceeds in two steps: 1) TNM-A binds to the membrane surface through direct interaction with sterols and 2) accumulated TNM-A modifies the local membrane curvature in a concentration-dependent manner, resulting in dramatic membrane morphological changes and membrane disruption.

    DOI: 10.1016/j.bbamem.2016.03.019

  • Lipid Interactions and Organization in Complex Bilayer Membranes 査読

    Oskar Engberg, Tomokazu Yasuda, Victor Hautala, Nobuaki Matsumori, Thomas K.M. Nyholm, Michio Murata, J. Peter Slotte

    Biophysical Journal   110 ( 7 )   1563 - 1573   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Bilayer lipids influence the lateral structure of the membranes, but the relationship between lipid properties and the lateral structure formed is not always understood. Model membrane studies on bilayers containing cholesterol and various phospholipids (PLs) suggest that high and low temperature melting PLs may segregate, especially in the presence of cholesterol. The effect of different PL headgroups on lateral structure of bilayers is also not clear. Here, we have examined the formation of lateral heterogeneity in increasingly complex (up to five-component) multilamellar bilayers. We have used time-resolved fluorescence spectroscopy with domain-selective fluorescent probes (PL-conjugated trans-parinaric acid), and 2H NMR spectroscopy with site or perdeuterated PLs. We have measured changes in bilayer order using such domain-selective probes both as a function of temperature and composition. Our results from time-resolved fluorescence and 2H NMR showed that in ternary bilayers, acyl chain order and thermostability in sphingomyelin-rich domains were not affected to any greater extent by the headgroup structure of the monounsaturated PLs (phosphatidylcholine, phosphatidylethanolamine, or phosphatidylserine) in the bilayer. In the complex five-component bilayers, we could not detect major differences between the different monounsaturated PLs regarding cholesterol-induced ordering. However, cholesterol clearly influenced deuterated N-palmitoyl sphingomyelin differently than the other deuterated PLs, suggesting that cholesterol favored N-palmitoyl sphingomyelin over the other PLs. Taken together, both the fluorescence spectroscopy and 2H NMR data suggest that the complex five-component membranes displayed lateral heterogeneity, at least in the lower temperature regimen examined.

    DOI: 10.1016/j.bpj.2015.12.043

  • TmDOTA as versatile thermometer compound for solid-state NMR of hydrated lipid bilayer membranes 査読

    Yuichi Umegawa, Yuya Tanaka, Nobuaki Matsumori, Michio Murata

    Magnetic Resonance in Chemistry   54 ( 3 )   227 - 233   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recent advances in solid-state nuclear magnetic resonance (NMR) techniques, such as magic angle spinning and high-power decoupling, have dramatically increased the sensitivity and resolution of NMR. However, these NMR techniques generate extra heat, causing a temperature difference between the sample in the rotor and the variable temperature gas. This extra heating is a particularly crucial problem for hydrated lipid membrane samples. Thus, to develop an NMR thermometer that is suitable for hydrated lipid samples, thulium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (TmDOTA) was synthesized and labeled with 13C (i.e., 13C-TmDOTA) to increase the NMR sensitivity. The complex was mixed with a hydrated lipid membrane, and the system was subjected to solid-state NMR and differential scanning calorimetric analyses. The physical properties of the lipid bilayer and the quality of the NMR spectra of the membrane were negligibly affected by the presence of 13C-TmDOTA, and the 13C chemical shift of the complex exhibited a large-temperature dependence. The results demonstrated that 13C-TmDOTA could be successfully used as a thermometer to accurately monitor temperature changes induced by 1H decoupling pulses and/or by magic angle spinning and the temperature distribution of the sample inside the rotor. Thus, 13C-TmDOTA was shown to be a versatile thermometer for hydrated lipid assemblies.

    DOI: 10.1002/mrc.4371

  • Sterol-dependent membrane association of the marine sponge-derived bicyclic peptide Theonellamide A as examined by1H NMR 査読

    Kimberly Cornelio, Rafael Atillo Espiritu, Yasuto Todokoro, Shinya Hanashima, Masanao Kinoshita, Nobuaki Matsumori, Michio Murata, Shinichi Nishimura, Hideaki Kakeya, Minoru Yoshida, Shigeki Matsunaga

    Bioorganic and Medicinal Chemistry   24 ( 21 )   5235 - 5242   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Theonellamide A (TNM-A) is an antifungal bicyclic dodecapeptide isolated from a marine sponge Theonella sp. Previous studies have shown that TNM-A preferentially binds to 3β-hydroxysterol-containing membranes and disrupts membrane integrity. In this study, several1H NMR-based experiments were performed to investigate the interaction mode of TNM-A with model membranes. First, the aggregation propensities of TNM-A were examined using diffusion ordered spectroscopy; the results indicate that TNM-A tends to form oligomeric aggregates of 2–9 molecules (depending on peptide concentration) in an aqueous environment, and this aggregation potentially influences the membrane-disrupting activity of the peptide. Subsequently, we measured the1H NMR spectra of TNM-A with sodium dodecyl sulfate-d25(SDS-d25) micelles and small dimyristoylphosphatidylcholine (DMPC)-d54/dihexanoylphosphatidylcholine (DHPC)-d22bicelles in the presence of a paramagnetic quencher Mn2+. These spectra indicate that TNM-A poorly binds to these membrane mimics without sterol and mostly remains in the aqueous media. In contrast, broader1H signals of TNM-A were observed in 10 mol % cholesterol-containing bicelles, indicating that the peptide efficiently binds to sterol-containing bilayers. The addition of Mn2+to these bicelles also led to a decrease in the relative intensity and further line-broadening of TNM-A signals, indicating that the peptide stays near the surface of the bilayers. A comparison of the relative signal intensities with those of phospholipids showed that TNM-A resides in the lipid–water interface (close to the C2′ portion of the phospholipid acyl chain). This shallow penetration of TNM-A to lipid bilayers induces an uneven membrane curvature and eventually disrupts membrane integrity. These results shed light on the atomistic mechanism accounting for the membrane-disrupting activity of TNM-A and the important role of cholesterol in its mechanism of action.

    DOI: 10.1016/j.bmc.2016.08.043

  • Formation of Gel-like Nanodomains in Cholesterol-Containing Sphingomyelin or Phosphatidylcholine Binary Membrane As Examined by Fluorescence Lifetimes and 2H NMR Spectra 査読

    Tomokazu Yasuda, Nobuaki Matsumori, Hiroshi Tsuchikawa, Max Lönnfors, Thomas K M Nyholm, J. Peter Slotte, Michio Murata

    Langmuir   31 ( 51 )   13783 - 13792   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In this study, we measured the time-resolved fluorescence of trans-parinaric acid (tPA), steady-state fluorescence anisotropy of diphenylhexatriene (DPH), and 2H NMR of 10,10-d2-stearoyl lipids in stearoyl sphingomyelin with cholesterol (SSM/Chol) and l-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine with Chol (PSPC/Chol) binary membranes. The results suggest that the membrane order obtained from the fluorescence experiments shows a similar temperature dependency as those of the 2H NMR data. More importantly, the time-resolved fluorescence data implied the presence of at least two types of domains, cholesterol-poor gel-like domains (CPGLD) and cholesterol-enriched liquid-ordered (Lo) domains. These domains appear on a nano-to-micro second time scale for both SSM-Chol and PSPC-Chol membranes. The relative size of the gel-like domain was also estimated from the temperature-dependent lifetime measurements and 2H NMR spectral changes. The results imply that the size of the gel-like domains is very small, probably on the nanometer scale, and smaller in SSM-Chol membrane than those in PSPC-Chol bilayers, which could account for the higher thermal stability of SM-Chol membranes. The present study demonstrates that gel-like nanodomains occur in SM-Chol binary membrane even with Chol content of over 33 mol %, which has been thought to consist exclusively of Lo phase, implying that not only Lo domains but also gel-like nanodomains are important for formation of lipid-ordered phase in SM-Chol and PC-Chol membranes.

    DOI: 10.1021/acs.langmuir.5b03566

  • Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane 査読 国際誌

    松森 信明

    BIOORGANIC & MEDICINAL CHEMISTRY   23 ( 17 )   5782 - 5788   2015年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bmc.2015.07.009

  • Bioactive Structure of Membrane Lipids and Natural Products Elucidated by a Chemistry-Based Approach 査読

    Michio Murata, Shigeru Sugiyama, Shigeru Matsuoka, Nobuaki Matsumori

    Chemical Record   15 ( 4 )   675 - 690   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Determining the bioactive structure of membrane lipids is a new concept, which aims to examine the functions of lipids with respect to their three-dimensional structures. As lipids are dynamic by nature, their "structure" does not refer solely to a static picture but also to the local and global motions of the lipid molecules. We consider that interactions with lipids, which are completely defined by their structures, are controlled by the chemical, functional, and conformational matching between lipids and between lipid and protein. In this review, we describe recent advances in understanding the bioactive structures of membrane lipids bound to proteins and related molecules, including some of our recent results. By examining recent works on lipid-raft-related molecules, lipid-protein interactions, and membrane-active natural products, we discuss current perspectives on membrane structural biology. Information on the bioactive structure of lipids is essential to gain deeper insight into biological membranes. As lipids are dynamic by nature, their "structure" does not refer solely to a static picture but also to the local and global motions of the lipid molecules. By examining recent work on lipid-raft-related molecules, lipid-protein interactions, and membrane-active natural products, we discuss current perspectives on membrane structural biology.

    DOI: 10.1002/tcr.201402097

  • Novel Raman-tagged sphingomyelin that closely mimics original raft-forming behavior 査読 国際誌

    松森 信明

    BIOORGANIC & MEDICINAL CHEMISTRY   23 ( 13 )   2015年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bmc.2015.05.014

  • Novel Raman-tagged sphingomyelin that closely mimics original raft-forming behavior 査読 国際誌

    松森 信明

    BIOORGANIC & MEDICINAL CHEMISTRY   23 ( 13 )   2989 - 2994   2015年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bmc.2015.05.014

  • Stereoselective synthesis of the head group of archaeal phospholipid PGP-Me to investigate bacteriorhodopsin-lipid interactions 査読 国際誌

    松森 信明

    ORGANIC & BIOMOLECULAR CHEMISTRY   13 ( 41 )   10279 - 10284   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1039/c5ob01252j

  • Orientation and Order of the Amide Group of Sphingomyelin in Bilayers Determined by Solid-State NMR 査読

    Nobuaki Matsumori, Toshiyuki Yamaguchi, Yoshiko Maeta, Michio Murata

    Biophysical Journal   108 ( 12 )   2816 - 2824   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sphingomyelin (SM) and cholesterol (Chol) are considered essential for the formation of lipid rafts; however, the types of molecular interactions involved in this process, such as intermolecular hydrogen bonding, are not well understood. Since, unlike other phospholipids, SM is characterized by the presence of an amide group, it is essential to determine the orientation of the amide and its order in the lipid bilayers to understand the nature of the hydrogen bonds in lipid rafts. For this study, 1′-13C-2-15N-labeled and 2′-13C-2-15N-labeled SMs were prepared, and the rotational-axis direction and order parameters of the SM amide in bilayers were determined based on 13C and 15N chemical-shift anisotropies and intramolecular 13C-15N dipole coupling constants. Results revealed that the amide orientation was minimally affected by Chol, whereas the order was enhanced significantly in its presence. Thus, Chol likely promotes the formation of an intermolecular hydrogen-bond network involving the SM amide without significantly changing its orientation, providing a higher order to the SM amide. To our knowledge, this study offers new insight into the significance of the SM amide orientation with regard to molecular recognition in lipid rafts, and therefore provides a deeper understanding of the mechanism of their formation.

    DOI: 10.1016/j.bpj.2015.05.011

  • Deuterium NMR of Raft Model Membranes Reveals Domain-Specific Order Profiles and Compositional Distribution 査読

    Tomokazu Yasuda, Hiroshi Tsuchikawa, Michio Murata, Nobuaki Matsumori

    Biophysical Journal   108 ( 10 )   2502 - 2506   2015年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In this report, we applied site-specifically deuterated N-stearoylsphingomyelins (SSMs) to raft-exhibiting ternary mixtures containing SSM, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and cholesterol (Chol) and successfully acquired deuterium quadrupole coupling profiles of SSM from liquid-ordered (Lo) and liquid-disordered (Ld) domains. To our knowledge, this is the first report that shows detailed lipid chain dynamics separately and simultaneously obtained from coexisting Lo and Ld domains. We also found that the quadrupole profile of the Lo phase in the ternary system was almost identical to that in the SSM-Chol binary mixture, suggesting that the order profile of the binary system is essentially applicable to more complicated membrane systems in terms of the acyl chain order. We also demonstrated that 2H NMR spectroscopy, in combination with organic synthesis of deuterated components, could be used to reveal the accurate mole fractions of each component distributed in the Lo and Ld domains. As compared with the reported tie-line analysis of phase diagrams, the merit of our 2H NMR analysis is that the domain-specific compositional fractions are directly attainable without experimental complexity and ambiguity. The accurate compositional distributions as well as lipid order profiles in ternary mixtures are relevant to understanding the molecular mechanism of lipid raft formation.

    DOI: 10.1016/j.bpj.2015.04.008

  • Modification of Bafilomycin Structure to Efficiently Synthesize Solid-State NMR Probes that Selectively Bind to Vacuolar-Type ATPase 査読 国際誌

    松森 信明

    CHEMISTRY-AN ASIAN JOURNAL   10 ( 4 )   2015年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/asia.201403299

  • Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane 査読

    Tomoya Yamamoto, Yuichi Umegawa, Hiroshi Tsuchikawa, Nobuaki Matsumori, Shinya Hanashima, Michio Murata, Resul Haser, Bernard J. Rawlings, Patrick Caffrey

    Bioorganic and Medicinal Chemistry   23 ( 17 )   5782 - 5788   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B (AmB) is a polyene macrolide antibiotic widely used to treat mycotic infections. In this paper, we focus on the role of the polyol moiety of AmB in sterol selectivity using 7-oxo-AmB, 7α-OH-AmB, and 7β-OH-AmB. The 7-OH analogs were prepared from 7-oxo-AmB. Their K+ flux activity in liposomes showed that introduction of an additional ketone or hydroxy group on the polyol moiety reduces the original activity. Conformational analyses of these derivatives indicated that intramolecular hydrogen-bonding network possibly influenced the conformational rigidity of the macrolactone ring, and stabilized the active conformation in the membrane. Additionally, the flexible polyol leads to destabilization of the whole macrolactone ring conformation, resulting in a loss of sterol selectivity.

    DOI: 10.1016/j.bmc.2015.07.009

  • Phosphatidylcholine bearing 6,6-dideuterated oleic acid: A useful solid-state H-2 NMR probe for investigating membrane properties 査読 国際誌

    松森 信明

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   25 ( 2 )   2015年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bmcl.2014.11.072

  • Erratum Stereoselective synthesis of the head group of archaeal phospholipid PGP-Me to investigate bacteriorhodopsin-lipid interactions (Organic and Biomolecular Chemistry (015) DOI:10.1039/ c5ob01252j) 査読

    Jin Cui, Satoshi Kawatake, Yuichi Umegawa, Sébastien Lethu, Masaki Yamagami, Shigeru Matsuoka, Fuminori Sato, Nobuaki Matsumori, Michio Murata

    Organic and Biomolecular Chemistry   13 ( 42 )   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1039/c5ob90166a

  • Axial hydrogen at C7 position and bumpy tetracyclic core markedly reduce sterol's affinity to amphotericin B in membrane 査読

    Yasuo Nakagawa, Yuichi Umegawa, Kenichi Nonomura, Naohiro Matsushita, Tetsuro Takano, Hiroshi Tsuchikawa, Shinya Hanashima, Tohru Oishi, Nobuaki Matsumori, Michio Murata

    Biochemistry   54 ( 2 )   303 - 312   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The interaction of amphotericin B (AmB) with fungal ergosterol (Erg) is stronger than its interaction with mammalian cholesterol (Cho), and this property of AmB as an antifungal drug is thought to be responsible for its selective toxicity toward fungi. However, the mechanism by which AmB recognizes the structural differences between sterols, particularly minor difference in the sterol alicyclic portion, is largely unknown. Thus, to investigate the mode of interaction between AmB and the sterol core, we assessed the affinity of AmB to various sterols with different alicyclic structures. Ion flux assays and UV spectral measurements clearly revealed the importance of the Δ7-double bond of the sterol B-ring for interaction with the drug. AmB showed lower affinity for triene sterols, which have double bonds at the Δ5, Δ7, and Δ9 positions. Intermolecular distance measurements by 13C{19F} rotational echo double resonance (REDOR) revealed that the AmB macrolide ring is in closer contact with the steroid core of Erg than it is with the Cho core in the membrane. Conformational analysis suggested that an axial hydrogen atom at C7 of Δ5-sterol (2, 6) and the protruded A-ring of Δ5,7,9-sterol (4, 8) sterically hampered face-to-face contact between the van der Waals surface of the sterol core and the macrolide of AmB. These results further suggest that the α-face of sterol alicycle interacts with the flat macrolide structure of AmB.

    DOI: 10.1021/bi5012942

  • Direct and Stereospecific Interaction of Amphidinol 3 with Sterol in Lipid Bilayers

    松森 信明

    BIOCHEMISTRY   53 ( 20 )   2014年5月

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    記述言語:英語  

    DOI: 10.1021/bi5002932

  • Effect of Sterol Side Chain on Ion Channel Formation by Amphotericin B in Lipid Bilayers 査読 国際誌

    松森 信明

    BIOCHEMISTRY   53 ( 19 )   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1021/bi500122c

  • Structure and Interaction in Lipid Bilayers Analyzed Using Bicelles 招待 査読

    松森 信明

    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN   72 ( 5 )   2014年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

  • Coexistence of two liquid crystalline phases in dihydrosphingomyelin and dioleoylphosphatidylcholine binary mixtures 査読 国際誌

    松森 信明

    BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES   1838 ( 5 )   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbamem.2014.01.017

  • Design and Synthesis of 24-Fluorinated Bafilomycin Analogue as an NMR Probe with Potent Inhibitory Activity to Vacuolar-type ATPase 査読 国際誌

    松森 信明

    CHEMISTRY LETTERS   43 ( 4 )   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1246/cl.131099

  • Structure and Biological Activity of 8-Deoxyheronamide C from a Marine-Derived Streptomyces sp.: Heronamides Target Saturated Hydrocarbon Chains in Lipid Membranes 査読 国際誌

    松森 信明

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   136 ( 14 )   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1021/ja500128u

  • Structure and interaction in lipid bilayers analyzed using bicelles 査読

    Nobuaki Matsumori

    Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry   72 ( 5 )   596 - 603   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although many non-peptidic drugs target biological membrane and membrane proteins, it is still difficult to determine the membrane-bound conformation of the drugs. To solve those problems, we have utilized bicelles as a membrane model, since the bicelles, which have planar lipid bilayer portions, are thought to be a more appropriate membrane model than micelles. Small-sized bicelles allow for liquid NMR measurements due to isotropic fast tumbling in solution. We have applied small bicelles to erythromycin A, salinomycin, and amphidinol 3, and determined their membrane-bound structures as well as their positions and orientations in the membranes using coupling constants, NOEs, and paramagnetic relaxation methods. Recently, we found that sphingomyelin, a major lipid constituent of lipid rafts, also forms bicelles, and established its conformation in the bicelles. These studies show the general utility of small bicelles for detailed conformation and orientation analysis of membrane-associated drugs and lipid molecules. We are now developing a bicelle-based crystallization method for membrane proteins, which will facilitate the cocrystalization of membrane proteins and hydrophobic drugs.

    DOI: 10.5059/yukigoseikyokaishi.72.596

  • Synthesis and structure revision of the C43-C67 part of amphidinol 3 査読

    Makoto Ebine, Mitsunori Kanemoto, Yoshiyuki Manabe, Yosuke Konno, Ken Sakai, Nobuaki Matsumori, Michio Murata, Tohru Oishi

    Organic Letters   15 ( 11 )   2846 - 2849   2013年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Stereoselective synthesis of the C43-C67 part of amphidinol 3 (AM3) and its C51-epimer was achieved starting from a common intermediate corresponding to the tetrahydropyran moiety of AM3, via asymmetric oxidations and Julia-Kocienski olefination. By comparing NMR data of the synthetic specimens with those of AM3, the absolute configuration at C51 of AM3 was revised from R to S.

    DOI: 10.1021/ol401176a

  • Characterization of the ordered phase formed by sphingomyelin analogues and cholesterol binary mixtures 査読

    Masanao Kinoshita, Sarah Goretta, Hiroshi Tsuchikawa, Nobuaki Matsumori, Michio Murata

    Biophysics (Japan)   9   37 - 49   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The influences of structural alterations of sphingomyelin (SM) on its interactions with cholesterol (chol) and on ordered phase formation were examined by density measurements and surface pressure vs. molecular area isotherm measurements. In addition, we quantitatively characterized the ordered phase formed in each SM and chol binary mixture on the basis of the molecular compressional modulus of SM (Cmol-1). Density measurements demonstrated that the ordered phase formation in threo- SM (tSM)/chol and dihydrosphingomyelin (DHSM)/chol binary bilayers shows similar chol concentration-dependency to that of natural erythro-SM (eSM)/chol bilayers; the ordered phase formation was completed in the presence of 25 mol% chol. In contrast, SM bearing a triple bond in the place of a double bond (tripleSM) required a greater concentration of chol to completely transform the bilayer into the ordered phase (at 40mol% chol). Surface pressure vs. molecular area isotherms showed that the DHSM molecule (Cmol-1=290mN/m) is more rigid than eSM (Cmol-1=240mN/m) above 30 mol% chol (in the ordered phase), although these values are similar (140- 150mN/m) in the absence of chol (liquid condensed phase). Most likely, the DHSM/chol mixture forms a more ordered membrane than the eSM/chol mixture does. Moreover, in the absence of chol, the rigidity of the tripleSM molecule (Cmol-1=250mN/m) is significantly higher as compared with that of the eSM molecule (Cmol-1=150mN/m), which is probably due to the presence of a triple bond.

    DOI: 10.2142/biophysics.9.37

  • Interaction between the marine sponge cyclic peptide theonellamide a and sterols in lipid bilayers as viewed by surface plasmon resonance and solid-state 2H nuclear magnetic resonance 査読

    Rafael Atillo Espiritu, Nobuaki Matsumori, Michio Murata, Shinichi Nishimura, Hideaki Kakeya, Shigeki Matsunaga, Minoru Yoshida

    Biochemistry   52 ( 14 )   2410 - 2418   2013年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Theonellamides (TNMs) are members of a distinctive family of antifungal and cytotoxic bicyclic dodecapeptides isolated from the marine sponge Theonella sp. Recently, it has been shown that TNMs recognize 3β-hydroxysterol- containing membranes, induce glucan overproduction, and damage cellular membranes. However, to date, the detailed mode of sterol binding at a molecular level has not been determined. In this study, to gain insight into the mechanism of sterol recognition of TNM in lipid bilayers, surface plasmon resonance (SPR) experiments and solid-state deuterium nuclear magnetic resonance (2H NMR) measurements were performed on theonellamide A (TNM-A). SPR results revealed that the incorporation of 10 mol % cholesterol or ergosterol into 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membranes significantly enhances the affinity of the peptide for the membrane, particularly in the initial binding to the membrane surface. These findings, together with the fact that binding of TNM-A to epicholesterol (3α-cholesterol)-containing liposomes and pure POPC liposomes was comparably weak, confirmed the preference of the peptide for the 3β-hydroxysterol-containing membranes. To further establish the formation of the complex of TNM-A with 3β-hydroxysterols in lipid bilayers, solid-state 2H NMR measurements were conducted using deuterium-labeled cholesterol, ergosterol, or epicholesterol. The 2H NMR spectra showed that TNM-A significantly inhibits the fast rotational motion of cholesterol and ergosterol, but not epicholesterol, therefore verifying the direct complexation between TNM-A and 3β-hydroxysterols in lipid bilayers. This study demonstrates that TNM-A directly recognizes the 3β-OH moiety of sterols, which greatly facilitates its binding to bilayer membranes.

    DOI: 10.1021/bi4000854

  • A novel sperm-activating and attracting factor from the ascidian Ascidia sydneiensis 査読

    Nobuaki Matsumori, Yuki Hiradate, Hajime Shibata, Tohru Oishi, Shuichi Shimma, Michisato Toyoda, Fumiaki Hayashi, Manabu Yoshida, Michio Murata, Masaaki Morisawa

    Organic Letters   15 ( 2 )   294 - 297   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A novel SAAF was isolated from the title ascidian. The structure was elucidated using the entire sample of 4 nmol, suggesting that the position of the OH group confers genus-specificity to sperm chemotaxis in ascidians. This study not only provides insight into the chemical tactics in sperm chemotaxis but demonstrates that the innovative techniques allow structure determination of natural products in trace amounts.

    DOI: 10.1021/ol303172n

  • Confirmation of the absolute configuration at C45 of amphidinol 3 査読

    Yoshiyuki Manabe, Makoto Ebine, Nobuaki Matsumori, Michio Murata, Tohru Oishi

    Journal of Natural Products   75 ( 11 )   2003 - 2006   2012年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphidinol 3 (AM3), a membrane-active agent isolated from the dinoflagellate Amphidinium klebsii, consists of a long carbon chain containing 25 stereogenic centers. Although the absolute configuration of AM3 was determined by extensive NMR analysis and degradation of the natural product, the partial structure corresponding to the tetrahydropyran ring system was found to be antipodal to that of karlotoxin 2, a structurally related compound recently isolated from the dinoflagellate Karlodinium veneficum. By extensive degradation of the natural product and conversion of the resulting alcohol to an MTPA ester, the absolute configuration at C45 of AM3 was confirmed to be R, supporting the originally proposed structure.

    DOI: 10.1021/np300604w

  • Possible conformation of amphotericin B dimer in membrane-bound assembly as deduced from solid-state NMR 査読

    Yuichi Umegawa, Takeshi Adachi, Nobuaki Matsumori, Michio Murata

    Bioorganic and Medicinal Chemistry   20 ( 19 )   5699 - 5704   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Aiming for structural analysis of amphotericin B (AmB) ion-channel assemblies in membrane, a covalent dimer was synthesized between 13C-labled AmB methyl ester and 19F-labled AmB. The dimer showed slightly weaker but significant biological activities against fungi and red blood cells compared with those of monomeric AmB. Then the dimer was subjected to 13C{19F}REDOR (Rotational-Echo Double Resonance) experiments in hydrated lipid bilayers. The obtained REDOR dephasing effects were explained by two components; a short 13C/19F distance (6.9 Å) accounting for 23% of the REDOR dephasing, and a longer one (14 Å) comprising the rest of the dephasing. The shorter distance is likely to reflect the formation of barrel-stave ion channel.

    DOI: 10.1016/j.bmc.2012.08.016

  • Effects of chemical modification of sphingomyelin ammonium group on formation of liquid-ordered phase 査読

    Sarah A. Goretta, Masanao Kinoshita, Shoko Mori, Hiroshi Tsuchikawa, Nobuaki Matsumori, Michio Murata

    Bioorganic and Medicinal Chemistry   20 ( 13 )   4012 - 4019   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sphingomyelin (SM) and cholesterol form microdomains called lipid rafts in cellular membranes. To develop a versatile fluorescent lipid probe, chemical modifications to both the hydrophobic and hydrophilic portions of SM are essential. Few reports describing SM probes with a fluorophore at the polar head group have been published. This study examined the effect of substitution on an ammonium moiety of SM on the membrane properties of SM. Two SM analogs with small propargyl and allyl groups on the quaternary nitrogen atom were synthesized and subjected to analysis using differential scanning calorimetry, fluorescent anisotropy, detergent solubilization, surface pressure, and density measurements. Results demonstrated that the two SM analogs retained the membrane properties of SM, including formation of an ordered phase and the ability to interact with cholesterol. A dansyl-substituted SM was prepared for fluorescent measurements. Dansyl-SM showed less of a propensity to form microdomains. These findings imply the potential application of N-substituted SMs as a raft-specific molecular probe.

    DOI: 10.1016/j.bmc.2012.05.015

  • Artificial ladder-shaped polyethers that inhibit maitotoxin-induced Ca 2+ influx in rat glioma C6 cells 査読

    Tohru Oishi, Keiichi Konoki, Rie Tamate, Kohei Torikai, Futoshi Hasegawa, Nobuaki Matsumori, Michio Murata

    Bioorganic and Medicinal Chemistry Letters   22 ( 11 )   3619 - 3622   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Maitotoxin (MTX) is a ladder-shaped polyether produced by the epiphytic dinoflagellate Gambierdiscus toxicus. It is known to elicit potent toxicity against mammals and induce influx of Ca2+ into cells. An artificial ladder-shaped polyether possessing a 6/7/6/6/7/6/6 heptacyclic ring system, which was designed for elucidating interactions with transmembrane proteins, was found to be the most potent inhibitor against MTX-induced Ca2+ influx that has ever been reported.

    DOI: 10.1016/j.bmcl.2012.04.053

  • Head-to-tail interaction between amphotericin b and ergosterol occurs in hydrated phospholipid membrane 査読

    Yuichi Umegawa, Yasuo Nakagawa, Kazuaki Tahara, Hiroshi Tsuchikawa, Nobuaki Matsumori, Tohru Oishi, Michio Murata

    Biochemistry   51 ( 1 )   83 - 89   2012年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B (AmB) is thought to exert its antifungal activity by forming an ion-channel assembly in the presence of ergosterol. In the present study we aimed to elucidate the mode of molecular interactions between AmB and ergosterol in hydrated phospholipid bilayers using the rotational echo double resonance (REDOR) spectra. We first performed 13C{ 19F}REDOR experiments with C14-19F-labeled AmB and biosynthetically 13C-labeled ergosterol and implied that both "head-to-head" and "head-to-tail" orientations occur for AmB-ergosterol interaction in the bilayers. To further confirm the "head-to-tail" pairing, 13C-labeled ergosterol at the dimethyl terminus (C26/C27) was synthesized and subjected to the REDOR measurements. The spectra unambiguously demonstrated the presence of a "head-to-tail" orientation for AmB-ergosterol pairing. In order to obtain information on the position of the dimethyl terminus of ergosterol in membrane, 13C{ 31P}REDOR were carried out using the labeled ergosterol and the phosphorus atom of a POPC headgroup. Significant REDOR dephasing was observed at the C26/C27 signal of ergosterol in the presence of AmB, but not in the absence of AmB, clearly indicating that the side-chain terminus of ergosterol in the AmB complex comes close to the bilayer surface.

    DOI: 10.1021/bi2012542

  • NMR-based conformational analysis of sphingomyelin in bicelles 査読

    Toshiyuki Yamaguchi, Takashi Suzuki, Tomokazu Yasuda, Tohru Oishi, Nobuaki Matsumori, Michio Murata

    Bioorganic and Medicinal Chemistry   20 ( 1 )   270 - 278   2012年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sphingomyelin (SM) is a common sphingolipid in mammalian membranes and is known to be substantially involved in cellular events such as the formation of lipid rafts. Despite its biological significance, conformation of SM in a membrane environment remains unclear because the noncrystalline property and anisotropic environment of lipid bilayers hampers the application of X-ray crystallography and NMR measurements. In this study, to elucidate the conformation of SM in membranes, we utilized bicelles as a substitute for a lipid bilayer membrane. First, we demonstrated through 31P NMR, 2H NMR, and dynamic light scattering experiments that SM forms both oriented and isotropic bicelles by changing the ratio of SM/dihexanoyl phosphatidylcholine. Then, we determined the conformation of SM in isotropic bicelles on the basis of coupling constants and NOE correlations in 1H NMR and found that the C2-C6 and amide groups of SM take a relatively rigid conformation in bicelles.

    DOI: 10.1016/j.bmc.2011.11.001

  • Design and synthesis of sphingomyelin-cholesterol conjugates and their formation of ordered membranes 査読

    Nobuaki Matsumori, Norio Tanada, Kohei Nozu, Hiroki Okazaki, Tohru Oishi, Michio Murata

    Chemistry - A European Journal   17 ( 31 )   8568 - 8575   2011年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A lipid raft is a cholesterol (Chol)-rich microdomain floating in a sea of lipid bilayers. Although Chol is thought to interact preferentially with sphingolipids such as sphingomyelin (SM), rather than with glycerophospholipids, the origin of the specific interaction has remained unresolved, primarily because of the high mobility of lipid molecules and weak intermolecular interactions. In this study, we synthesized SM-Chol conjugates with functionally designed linker portions to restrain Chol mobility and examined their formation of ordered membranes by a detergent insolubility assay, fluorescence anisotropy experiments, and fluorescence-quenching assay. In all of the tests, membranes prepared from the conjugates showed properties of ordered domains comparable to a SM-Chol (1:1) membrane. To gain insight into the structure of bilayers composed from the conjugates, we performed molecular dynamics simulations with 64 molecules of the conjugates, which suggested that the conjugates form a stable bilayer structure by bending at the linker portion and, mostly, reproduce the hydrogen bonds between the SM and Chol portions. These results imply that the molecular recognition between SM and Chol in an ordered domain is essentially reproduced by the conjugated molecules and, thus, demonstrates that these conjugate molecules could potentially serve as molecular probes for understanding molecular recognition in lipid rafts.

    DOI: 10.1002/chem.201100849

  • Channels formed by amphotericin B covalent dimers exhibit rectification 査読

    Minako Hirano, Yuko Takeuchi, Nobuaki Matsumori, Michio Murata, Toru Ide

    Journal of Membrane Biology   240 ( 3 )   159 - 164   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B (AmB) is a widely used antifungal antibiotic with high specificity for fungi. We previously synthesized several covalently conjugated AmB dimers to clarify the AmB channel structure. Among these dimers, that with an aminoalkyl linker was found to exhibit potent hemolytic activity. We continue this work by investigating the channel activity of the dimer, finding that all channels comprised of AmB dimers show rectification. The direction of the dimer channel in the membrane depended on the electric potential at which the dimer channel was formed. On the other hand, only about half the monomer channels showed rectification. In addition, these channels were easily switched from a rectified to a nonrectified state following voltage stimulation, indicating instability. We propose a model to describe the AmB channel structure that explains why AmB dimer channels necessarily show rectification.

    DOI: 10.1007/s00232-011-9354-x

  • Lysine proximity significantly affects glycation of lysine-containing collagen model peptides 査読

    Asuka Kitamura, Kouta Matsui, Keiichi Konoki, Nobuaki Matsumori, Michio Murata, Toru Kawakami, Saburo Aimoto

    Bioorganic and Medicinal Chemistry   19 ( 7 )   2125 - 2129   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Advanced glycation end products (AGE) are known to cause diabetes complications in hyperglycemia patients. In this study we prepared hetero-trimers of collagen model peptides comprising Ac-(Pro-Hyp-Gly) 5-Pro-Lys-Gly-(Pro-Hyp-Gly)5-Ala-NH2 (4) and Ac-(Pro-Hyp-Gly)11-Ala-NH2 (5) to investigate the clustering effect of lysine on AGE formation. The formation rate of carboxymethyllysine over several months was determined for the mixtures of peptides 4 and 5 at (3:0), (2:1) and (1:2) in the presence of glucose. The contents of carboxymethyllysine were significantly enhanced for (3:0) and (2:1) as compared with (1:2), suggesting that the proximity of lysine residues in the trimers accelerated formation of the AGE. Furthermore, a lysine dimerization moiety (GOLD) was identified for the first time from AGEs of glucose origin, which implied the significance of GOLD in oligomerization of collagens and other long-life proteins.

    DOI: 10.1016/j.bmc.2011.02.048

  • Conformations of spermine in adenosine triphosphate complex The structural basis for weak bimolecular interactions of major cellular electrolytes 査読

    Keisuke Maruyoshi, Toshiyuki Yamaguchi, Tetsuo Demura, Nobuaki Matsumori, Tohru Oishi, Michio Murata

    Chemistry - A European Journal   17 ( 17 )   4788 - 4795   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Selectively 2H- and 13C-labeled spermines (SPM) were efficiently synthesized and analyzed by NMR spectroscopy to determine the spin-spin coupling constants for six conformationally relevant bonds. SPM that is composed of three alkyl moieties, a butanylene, and two propanylene chains undergoes a conformational change when interacting with multivalent anions (e.g., adenosine triphosphate (ATP), ATP-Mg2+, and tripolyphosphate). Upon interaction with ATP, the C-C bonds, which affect the distance between the neighboring pairs of ammonium groups (i.e., N1/N5 and N5/N5′), increase the population of gauche rotamers by 17-20 % relative to those in the 4 HCl salt of SPM. However, the trend in increments of the gauche conformers for the SPM-ATP complex profoundly differs from that of the spermidine (SPD)-ATP complex. This implies that SPM may preferentially recognize the adenyl group of ATP rather than the tripolyphosphate moiety. This may account for the higher affinity of SPM to ATP-Mg2+ than with that of SPD, which chiefly interacts with β- and Î-phosphates and is easily replaced by Mg 2+. These results may provide a clue for the further understanding of the structural basis of polyamine biological functions. Spermines and spin: Spermines (SPM) labeled selectively with 2H and 13C were used to determine the spin-spin coupling constants for six conformationally relevant bonds. SPM revealed diverse conformational changes upon interaction with adenosine triphosphate (ATP), ATP-Mg2+, and tripolyphosphate (TPP, see graph).

    DOI: 10.1002/chem.201002759

  • Synthesis of 6-F-ergosterol and its influence on membrane-permeabilization of amphotericin B and amphidinol 3 査読

    Yusuke Kasai, Nobuaki Matsumori, Hiroyuki Ueno, Kenichi Nonomura, Shinya Yano, Murata Michio, Tohru Oishi

    Organic and Biomolecular Chemistry   9 ( 5 )   1437 - 1442   2011年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Two well-known antifungals, amphotericin B (AmB) and amphodinol 3 (AM3), are thought to exert antifungal activity by forming ion-permeable channels or pores together with sterol molecules. However, detailed molecular recognitions for AmB-sterol and AM3-sterol in lipid bilayers have yet to be determined. Toward 19F NMR-based investigation of the molecular recognition underlying their potent antifungal activity, we synthesized 6-fluoro-ergosterol in five steps via ring opening of (5α,6α)-epoxide of ergosterol acetate with using novel combination of TiF4 and n-Bu 4N+Ph3SiF2-. Then we evaluated its activity of promoting pore formation of AmB and AM3, and found that pore formation of AmB was barely promoted by 6-F-ergosterol in clear contrast to the dramatic promotion effect of unmodified ergosterol, whereas AM3 activity was markedly enhanced in the presence of 6-F-ergosterol, which was comparable to that of unmodified ergosterol. These results indicate that the introduction of an F atom at C6 position of ergosterol plays an inhibitory role in interacting with AmB, but it is not the case with AM3.

    DOI: 10.1039/c0ob00685h

  • Fluorinated cholesterol retains domain-forming activity in sphingomyelin bilayers 査読

    Nobuaki Matsumori, Horoki Okazaki, Kaoru Nomura, Michio Murata

    Chemistry and Physics of Lipids   164 ( 5 )   401 - 408   2011年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Lipid rafts are cholesterol (Chol)-rich microdomains floating in a sea of lipid bilayers. Chol is thought to interact preferentially with sphingolipids such as sphingomyelin (SM) rather than with glycerophospholipids, and this putative SM-Chol interaction is generally recognized as a requirement for raft formation. However, the presence of the specific interaction is still controversial, primarily because of the lack of useful molecular probes for scrutinizing this interaction. Recently, we reported that the dynamic properties of 6-F-Chol in DMPC bilayers are similar to those of unmodified Chol. Hence, in the present study, we first compared the roles of 6-F-Chol and Chol in SM bilayers through detergent insolubility, fluorescence polarization, and 2H NMR experiments. The results demonstrated that 6-F-Chol and Chol behave similarly in SM bilayers, whereas, in SM-DOPC membranes, 6-F-Chol is less effective in domain formation. Then, we analyzed the molecular orientation of 6-F-Chol in SM bilayers using solid-state NMR, and found that the dynamics and orientation of 6-F-Chol in SM bilayers are almost identical to those in DMPC bilayers. This supports the notion of the lack of a putative specific interaction between SM and Chol. Thus, this study demonstrates the utility of 6-F-Chol as a molecular probe for understanding molecular recognition in lipid rafts.

    DOI: 10.1016/j.chemphyslip.2011.05.007

  • Detection of Rap1A as a yessotoxin binding protein from blood cell membranes 査読

    Satoru Ujihara, Tohru Oishi, Ryota Mouri, Rie Tamate, Keiichi Konoki, Nobuaki Matsumori, Michio Murata, Yasukatsu Oshima, Naoyuki Sugiyama, Masaru Tomita, Yasushi Ishihama

    Bioorganic and Medicinal Chemistry Letters   20 ( 22 )   6443 - 6446   2010年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    As is the case with other ladder-shaped polyether compounds, yessotoxin is produced by marine dinoflagellate, and possesses various biological activities beside potent toxicity. To gain a better understanding of the molecular mechanism for high affinity between these polyethers and their binding proteins, which accounts for their powerful biological activities, we searched for its binding proteins from human blood cells by using the biotin-conjugate of desulfated YTX as a ligand. By a protein pull-down protocol with use of streptavidin beads, a band of specifically binding proteins was detected in SDS-PAGE. HPLC-tandem mass spectrometry (MS/MS) indicated that Rap 1A, one of Ras superfamily proteins, binds to the YTX-linked resins. Western blotting and surface plasmon resonance experiments further confirmed that Rap1A specifically binds to YTX with the KD value around 4 μM.

    DOI: 10.1016/j.bmcl.2010.09.080

  • 3D structures of membrane-associated small molecules as determined in isotropic bicelles 査読

    Nobuaki Matsumori, Michio Murata

    Natural Product Reports   27 ( 10 )   1480 - 1492   2010年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    About half of known bioactive organic molecules, including drugs, are known to target biological membranes and membrane proteins. Despite this, it has proven difficult to define the membrane-bound conformations of these molecules. In recent years, bicelles have been recognized as a more appropriate membrane model than micelles because their planar portion is composed of a lipid bilayer. Bicelles with a small diameter, termed isotropic or fast-tumbling bicelles, allow for high-resolution NMR measurements due to their high mobility in suspension, and therefore have become a versatile tool for structure studies of membrane-associated molecules. Following a brief description of the morphology and preparation of isotropic bicelles, we summarize their application to structural studies of membrane-bound peptides and small molecules, and then highlight our recent studies on the 3D structures of erythromycin A, salinomycin and amphidinol 3 using isotropic bicelles.

    DOI: 10.1039/c0np00002g

  • Sterol effect on interaction between amphidinol 3 and liposomal membrane as evidenced by surface plasmon resonance 査読

    Respati T. Swasono, Ryota Mouri, Nagy Morsy, Nobuaki Matsumori, Tohru Oishi, Michio Murata

    Bioorganic and Medicinal Chemistry Letters   20 ( 7 )   2215 - 2218   2010年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The affinity of amphidinol 3 (AM3) to phospholipid membranes in the presence and absence of sterol was examined by surface plasmon resonance (SPR) experiments. The results showed that AM3 has 1000 and 5300 times higher affinity for cholesterol- and ergosterol-containing liposomes, respectively, than those without sterol. The two-state reaction model well reproduced the sensor grams, which indicated that the interaction is composed of two steps, which correspond to binding to the membrane and internalization to form stable complexes.

    DOI: 10.1016/j.bmcl.2010.02.025

  • Structural reevaluations of amphidinol 3, a potent antifungal compound from dinoflagellate 査読

    Respati T. Swasono, Mitsunori Kanemoto, Nobuaki Matsumori, Tohru Oishi, Michio Murata

    Heterocycles   82 ( 2 )   1359 - 1369   2010年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Among other homologues, amphidinol 3 (AM3) is the most potent antifungal compound isolated from the dinoflagellate Amphidinium klebsii. AM3 undergoes conformational changes in organic solvents while it takes relatively fixed configuration in a membrane model. By using NMR data of peracetyl AM3, we were able to confirm the configuration of C50-C51 of AM3 which remained uncertain in our previous study.

    DOI: 10.3987/COM-10-S(E)86

  • Amphotericin B-induced ion flux is markedly attenuated in phosphatidylglycerol membrane as evidenced by a newly devised fluorometric method 査読

    Tetsuro Takano, Keiichi Konoki, Nobuaki Matsumori, Michio Murata

    Bioorganic and Medicinal Chemistry   17 ( 17 )   6301 - 6304   2009年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The effect of phospholipid head group on the membrane-permeabilizing activity of amphotericin B (AmB) was examined using 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomes and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol (POPG) liposomes. The activity of AmB was evaluated as K+ influx measured as pH change inside liposomes by fluorescent measurements of 2′,7′-bis(carboxyethyl)-4 or 5-carboxyfluorescein (BCECF). AmB showed prominent permeability in POPC liposomes, whereas hardly inducing ion flux in POPG membrane. POPC added to POPG liposomes as a minor constituent markedly enhanced membrane permeability, indicating the importance of a phosphonocholine group of PC for the drug's activity.

    DOI: 10.1016/j.bmc.2009.07.036

  • Direct interaction between amphotericin B and ergosterol in lipid bilayers as revealed by 2H NMR spectroscopy 査読

    Nobuaki Matsumori, Kazuaki Tahara, Hiroko Yamamoto, Atsushi Morooka, Mototsugu Doi, Tohru Oishi, Michio Murata

    Journal of the American Chemical Society   131 ( 33 )   11855 - 11860   2009年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although amphotericin B (AmB) is thought to exert its antifungal activity by forming transmembrane ion-permeable self-assemblies together with ergosterol, no previous study has directly proven AmB-ergosterol interaction. To establish the interaction, we measured 2H NMR using deuterium-labeled sterols and AmB. The 2H NMR spectra of deuterated ergosterol in palmitoyloleoylphosphatidylcholine (POPC) bilayers showed that fast axial diffusion of erogosterol was almost completely inhibited by the coexistence of AmB. Conversely, cholesterol mobility in POPC membrane was essentially unchanged with or without AmB. These results unequivocally demonstrate that ergosterol has significant interaction with AmB in POPC bilayers. In addition, we examined the mobility of AmB using deuterium-labeled AmB, and found that, although AmB is almost immobilized in sterol-free and cholesterol-containing POPC membranes, a certain ratio of AmB molecules acquires mobility in the presence of ergosterol. The similar mobility of AmB and ergosterol in POPC bilayers confirmed the idea of the direct intermolecular interaction between ergosterol and AmB.

    DOI: 10.1021/ja9033473

  • Ion channel complex of antibiotics as viewed by NMR 査読

    Michio Murata, Yusuke Kasai, Yuichi Umegawa, Naohiro Matsushita, Hiroshi Tsuchikawa, Nobuaki Matsumori, Tohru Oishi

    Pure and Applied Chemistry   81 ( 6 )   1123 - 1129   2009年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B (AmB) exerts its pharmacological effects by forming a barrel-stave assembly in fungal membranes. To examine the interaction between AmB and ergosterol or cholesterol, 13C- and 19F-labeled covalent conjugates were prepared and subjected to solidstate NMR measurements. Using rotor-synchronous double-resonance experiments such as rotational echo double resonance (REDOR) and RDX, we estimated the distance between the fluorine atom and its nearest carbon in the heptaene moiety to be less than 8.6 A ̊, indicating that the B ring of ergosterol comes close to the AmB polyene moiety. Conformational search of the AmB-ergosterol conjugate using the NMR-derived constraints suggested that ergosterol molecules surround the AmB assembly in contrast to the conventional image where ergosterol is inserted into AmB molecules. AmB-AmB bimolecular interaction was examined by using 13C- and 19F-labeled AmBs in dimyritoylphosphatidylcholine (DMPC) membrane without sterols. 13C- and 19F dipolar interactions deriving from both head-to-head and head-to-tail orientations were observed in the REDOR experiments. The interactions between AmB and acyl chains of the phospholipid were also detected.

    DOI: 10.1351/PAC-CON-08-08-37

  • Surface plasmon resonance-based detection of ladder-shaped polyethers by inhibition detection method 査読

    Ryota Mouri, Tohru Oishi, Kohei Torikai, Satoru Ujihara, Nobuaki Matsumori, Michio Murata, Yasukatsu Oshima

    Bioorganic and Medicinal Chemistry Letters   19 ( 10 )   2824 - 2828   2009年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ladder-shaped polyether (LSP) compounds represented by brevetoxins and ciguatoxins were largely discovered in association with seafood poisoning. Thus, a quick quantification method for LSPs is potentially important. We examined a surface plasmon resonance method using desulfated-yessotoxin (dsYTX) immobilized on a sensor chip and phosphodiesterase PDEII in a inhibition detection mode. Yessotoxin, brevetoxin B and synthetic LSP derivatives showed clear inhibition against PDEII binding to the immobilized dsYTX, by which their half inhibitory concentrations were successfully estimated. This inhibition method appeared to be superior in specificity to direct binding assays where binding proteins to LSP was immobilized on a sensor chip.

    DOI: 10.1016/j.bmcl.2009.03.103

  • Conformational change of spermidine upon interaction with adenosine triphosphate in aqueous solution 査読

    Keisuke Maruyoshi, Kaori Nonaka, Takeshi Sagane, Tetsuo Demura, Toshiyuki Yamaguchi, Nobuaki Matsumori, Tohru Oishi, Michio Murata

    Chemistry - A European Journal   15 ( 7 )   1618 - 1626   2009年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Endogenous polyamines, represented by putrescine, spermidine, and spermine, are known to exert their physiological functions by interacting with polyanionic biomolecules such as DNA, RNA, adenosine triphosphate (ATP), and phospholipids. Very few examples of conformation analysis have been reported for these highly flexible polymethylene compounds, mainly due to the lack of appropriate methodologies. To understand the molecular basis of the weak interaction between polyamines and polyanions that underlies their physiological functions, we aimed to elucidate the solution conformation of spermidine by using diastereospecifically deuterated and
    13
    C-labeled derivatives (1-7), which were designed to diagnose the orientation of seven conformationally relevant bonds in spermidine. 1H-1H and
    13
    C-1H NMR coupling constants (
    3
    J
    H,H
    and
    3
    J
    C,H
    ) were successfully determined for a spermidine-ATP complex. The relevant coupling constants markedly decreased upon complexation. The results reveal that spermidine, when interacting with ATP, undergoes changes that make the conformation more bent and forms the complex with the triphosphate part of ATP in an orientation-sensitive manner.

    DOI: 10.1002/chem.200801961

  • Synthesis of 25- 13c-amphotericin B methyl ester A molecular probe for solid-state NMR measurements 査読

    Naohiro Matsushita, Yukiko Matsuo, Hiroshi Tsuchikawa, Nobuaki Matsumori, Michio Murata, Tohru Oishi

    Chemistry Letters   38 ( 2 )   114 - 115   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A 13C-labeled amphotericin B (AmB) derivative was synthesized based on a hybrid strategy combining chemical synthesis with degradation of a natural product through successive cross-coupling reactions and macrolactonization. The specimen regiospecifically 13C-labeled (99% enrichment) at C25 position corresponding to the polyene moiety would be a powerful tool for structural analysis of the molecular assembly formed by AmB based on solid-state NMR measurements.

    DOI: 10.1246/cl.2009.114

  • Accurate measurement of vicinal carbon-hydrogen coupling constants via ammonium nitrogen based on HMBC experiments 査読

    Toshiyuki Yamaguchi, Keisuke Marayoshi, Nobuaki Matsumori, Michio Murata

    Chemistry Letters   37 ( 11 )   1172 - 1173   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Vicinal spin-spin coupling constants frequently used for conformation analysis were determined for ammonium-containing 13C-N-C- 1H systems by using HMBC. 1-Deoxynojirimycin hydrochloride provided an appropriate system for measuring the antiperiplanar and gauche interactions, which were determined to be 7.3 and 1.6 Hz, respectively.

    DOI: 10.1246/cl.2008.1172

  • Structure of membrane-bound amphidinol 3 in isotropic small bicelles 査読

    Toshihiro Houdai, Nobuaki Matsumori, Michio Murata

    Organic Letters   10 ( 19 )   4191 - 4194   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    (Chemical Equation Presented) Amphidinol 3 (AM3) exhibits a potent membrane permeabilizing activity by forming pores in biological membranes. We examined the conformation and location of AM3 using Isotropic bicelles, a more natural membrane model than micelles. The results show that AM3 takes turn structures at the two tetrahydropyran rings. Most of the hydrophilic region of the molecule is predominantly present in the surface, while the hydrophobic polyolefin penetrates in the bicelle interior.

    DOI: 10.1021/ol8016337

  • Structural features of dinoflagellate toxins underlying biological activity as viewed by NMR 査読

    Michio Murata, Nobuaki Matsumori, Keiichi Konoki, Tohru Oishi

    Bulletin of the Chemical Society of Japan   81 ( 3 )   307 - 319   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Marine dinoflagellates are a rich source of structurally and biologically intriguing secondary metabolites. Among those, maitotoxin may be one of the best known examples, which is the largest natural product known to date and possesses the most potent toxicity known amongst non-proteinaceous compounds. Structural studies of maitotoxin are reviewed with a particular focus on the configuration and mode of action of this unique toxin. In addition, there are many marine natural products which bind to biomembranes to exert their biological activities. To gain a better understanding of their mode of action, conformation, and bimoleeular interaction occurring in biomembranes are particularly important. Recent results from NMR studies of membrane systems in the authors' group are reviewed briefly.

    DOI: 10.1246/bcsj.81.307

  • Interaction of ladder-shaped polyethers with transmembrane α-helix of glycophorin A as evidenced by saturation transfer difference NMR and surface plasmon resonance 査読

    Satoru Ujihara, Tohru Oishi, Kohei Torikai, Keiichi Konoki, Nobuaki Matsumori, Michio Murata, Yasukatsu Oshima, Saburo Aimoto

    Bioorganic and Medicinal Chemistry Letters   18 ( 23 )   6115 - 6118   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ladder-shaped polyether (LSP) compounds are thought to interact with transmembrane α-helices, but direct evidence has scarcely obtained for these interactions. We adopted a transmembrane α-helix of glycophorin A, and quantitatively evaluated its interaction with LSPs such as yessotoxin (YTX), desulfated YTX and artificial LSPs, using surface plasmon resonance and saturation transfer difference NMR. As a result, dissociation constants (KD) of YTX and desulfated YTX to a transmembrane domain peptide of glycophorin A were determined to be in the submillimolar range. Furthermore, in saturation transfer difference NMR, the signals at the polyene side chain and the angular methyl groups of YTX were significantly attenuated, which probably comprised an interacting interface of LSPs with a transmembrane α-helix. These results suggest that hydrophobic interaction plays an important role in molecular recognition of the α-helix peptide by LSPs.

    DOI: 10.1016/j.bmcl.2008.10.020

  • Ergosterol increases the intermolecular distance of amphotericin B in the membrane-bound assembly as evidenced by solid-state NMR 査読

    Yuichi Umegawa, Nobuaki Matsumori, Tohru Oishi, Michio Murata

    Biochemistry   47 ( 51 )   13463 - 13469   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B (AmB) exerts its antifungal activity by forming ion-permeable assemblies across lipid bilayers. To investigate AmB-AmB bimolecular interactions in the assembly, we carried out 13C{ 19F}REDOR experiments using 14-19F- and 13C41-labeled AmBs in sterol-containing and sterol-free palmitoyloleoylphosphatidylcholine (POPC) membranes and measured the average distance between the labeled sites of AmBs in membrane-bound forms. The REDOR results suggested that the intermolecular distance of AmB molecules is significantly increased in the ergosterol membrane as compared with the cholesterol membrane. This sterol-dependent change was supported by the UV spectra of AmB in lipid bilayers, in which the excitonic absorption band arising from the aggregated state of AmB shifted to longer wavelength in ergosterol-containing POPC membrane. The REDOR experiments also disclosed that the head-to-head orientation of AmB is predominant in both of the sterol-containing membranes and AmB-POPC interaction was detected only in the ergosterol membrane. Ergosterol significantly influences the interactions between AmB molecules as well as those between AmB and POPC, which may facilitate formation of ion-permeable channels in ergosterol-containing membrane.

    DOI: 10.1021/bi801875y

  • Convergent synthesis and biological activity of the WXYZA′B′ C′ ring system of maitotoxin 査読

    Tohru Oishi, Futoshi Hasegawa, Kohei Torikai, Keiichi Konoki, Nobuaki Matsumori, Michio Murata

    Organic Letters   10 ( 16 )   3599 - 3602   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    (Chemical Equation Presented) The WXYZA′B′C′ ring system (1) of maitotoxin (MTX) was synthesized in a convergent manner via successive coupling of the W, Z, and C′ ring fragments through construction of the XY and A′B′ ring systems. The synthetic segment 1 blocked the hemolytic activity elicited by MTX.

    DOI: 10.1021/ol801369g

  • Combinatorial synthesis of the 1,5-polyol system based on cross metathesis Structure revision of amphidinol 3 査読

    Tohru Oishi, Mitsunori Kanemoto, Respati Swasono, Nobuaki Matsumori, Michio Murata

    Organic Letters   10 ( 22 )   5203 - 5206   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    (Chemical Equation Presented) Combinatorial synthesis of a 1,5-polyol system corresponding to the C1-C14 unit of amphidinol 3 (AM3) and its diastereomers was achieved via chemoselective cross metathesis as the key step. Comparison of 13C NMR data of the synthetic specimens with that of AM3 led to a controversy regarding the originally proposed structure. From GC-MS analysis of the degradation product, the absolute configuration at C2 of AM3 has been revised to be R.

    DOI: 10.1021/ol802168r

  • Design and synthesis of ladder-shaped tetracyclic, heptacyclic, and decacyclic ethers and evaluation of the interaction with transmembrane proteins 査読

    Kohei Torikai, Tohru Oishi, Satoru Ujihara, Nobuaki Matsumori, Keiichi Konoki, Michio Murata, Saburo Aimoto

    Journal of the American Chemical Society   130 ( 31 )   10217 - 10226   2008年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ladder-shaped polyether (LSP) toxins represented by brevetoxins and Ciguatoxins are thought to bind to transmembrane (TM) proteins. To elucidate the interactions of LSPs with TM proteins, we have synthesized artificial ladder-shaped polyethers (ALPs) containing 6/7/6/6 tetracyclic, 6/7/6/6/7/6/6 heptacyclic, and 6/7/6/6/7/6/6/7/6/6 decacyclic systems, based on the convergent method via α-cyano ethers. The ALPs possessing the simple iterative structure with different numbers of rings would be useful for structure-activity relationship studies on the molecular length, which is supposed to be important when naturally occurring LSPs elicit their toxicity. Two series of ALPs were prepared to evaluate the hydrophilic or hydrophobic effects of the side chains: (i) both sides were functionalized as diols (A series), and (ii) one side remained as diol and the other side was protected as benzyl ethers (B series). To examine the interaction of these ALPs with TM proteins, dissociation of glycophorin A (GpA) dimers into monomers was evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The heptacyclic ether (ALP7B) elicited the most potent activity in the presence of 2% SDS buffer, whereas the decacyclic ether (ALP10A) exhibited an intriguing phenomenon to induce precipitation of GpA in a dose-dependent manner, under the low concentration of SDS (0.03%). ALP10A also induced precipitation of integrin α 1β1, a TM protein known to form heterodimers in the lipid bilayer membranes. The different activities among the ALPs can be accounted for by the concept of "hydrophobic matching" that is, lengths of the hydrophobic region including the side chains of ALP7B and ALP10A are ca. 25 Å, which match the lengths of the hydrophobic region of α-helical TM proteins, as well as the hydrophobic thickness of lipid bilayer membranes. The concept of the hydrophobic matching would be a clue to understanding the interaction between LSPs and TM proteins, and also a guiding principle to design ALPs possessing potent affinities with TM proteins.

    DOI: 10.1021/ja801576v

  • Complex formation of amphotericin B in sterol-containing membranes as evidenced by surface plasmon resonance 査読

    Ryota Mouri, Keiichi Konoki, Nobuaki Matsumori, Tohru Oishi, Michio Murata

    Biochemistry   47 ( 30 )   7807 - 7815   2008年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B (AmB) is a membrane-active antibiotic that increases the permeability of fungal membranes. Thus, the dynamic process of its interaction with membranes poses intriguing questions, which prompted us to elaborate a quick and reliable method for real-time observation of the drug's binding to phospholipid liposomes. We focused on surface plasmon resonance (SPR) and devised a new modification method of sensor chips, which led to a significant reduction in the level of nonspecific binding of the drug in a control lane. With this method in hand, we examined the affinity of AmB for various membrane preparations. As expected, AmB exhibited much higher affinity for sterol-containing palmitoyloleoylphosphatidylcholine membranes than those without sterol. The sensorgrams recorded under various conditions partly fitted theoretical curves, which were based on three interaction models. Among those, a two-state reaction model reproduced well the sensorgram of AmB binding to an ergosterol-containing membrane; in this model, two states of membrane-bound complexes, AB and AB*, are assumed, which correspond to a simple binding to the surface of the membrane (AB) and formation of another assembly in the membrane (AB*) such as an ion channel complex. Kinetic analysis demonstrated that the association constant in ergosterol-containing POPC liposomes is larger by 1 order of magnitude than that in the cholesterol-containing counterpart. These findings support the previous notion that ergosterol stabilizes the membrane-bound assembly of AmB.

    DOI: 10.1021/bi800334p

  • Roles of integral protein in membrane permeabilization by amphidinols 査読

    Nagy Morsy, Keiichi Konoki, Toshihiro Houdai, Nobuaki Matsumori, Tohru Oishi, Michio Murata, Saburo Aimoto

    Biochimica et Biophysica Acta - Biomembranes   1778 ( 6 )   1453 - 1459   2008年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphidinols (AMs) are a group of dinoflagellate metabolites with potent antifungal activity. As is the case with polyene macrolide antibiotics, the mode of action of AMs is accounted for by direct interaction with lipid bilayers, which leads to formation of pores or lesions in biomembranes. However, it was revealed that AMs induce hemolysis with significantly lower concentrations than those necessary to permeabilize artificial liposomes, suggesting that a certain factor(s) in erythrocyte membrane potentiates AM activity. Glycophorin A (GpA), a major erythrocyte protein, was chosen as a model protein to investigate interaction between peptides and AMs such as AM2, AM3 and AM6 by using SDS-PAGE, surface plasmon resonance, and fluorescent-dye leakages from GpA-reconstituted liposomes. The results unambiguously demonstrated that AMs have an affinity to the transmembrane domain of GpA, and their membrane-permeabilizing activity is significantly potentiated by GpA. Surface plasmon resonance experiments revealed that their interaction has a dissociation constant of the order of 10 μM, which is significantly larger than efficacious concentrations of hemolysis by AMs. These results imply that the potentiation action by GpA or membrane integral peptides may be due to a higher affinity of AMs to protein-containing membranes than that to pure lipid bilayers.

    DOI: 10.1016/j.bbamem.2008.01.018

  • Orientation of fluorinated cholesterol in lipid bilayers analyzed by 19F tensor calculation and solid-state NMR 査読

    Nobuaki Matsumori, Yusuke Kasai, Tohru Oishi, Michio Murata, Kaoru Nomura

    Journal of the American Chemical Society   130 ( 14 )   4757 - 4766   2008年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    6-F-cholesterol was reported to exhibit biological and interfacial properties similar to unmodified cholesterol. We have also found that 6-F-cholesterol mimicked the cholesterol activity observed in the systems of amphotericin B and lipid rafts. However, to use 6-F-cholesterol as a molecular probe to explore molecular recognition in membranes, it is indispensable to have detailed knowledge of the dynamic and orientation properties of the molecule in membrane environments. In this paper, we present the molecular orientation of 6-F-cholesterol (30 mol %) in dimyristoylphosphatidylcholine (DMPC) bilayers revealed by combined use of 19F chemical shift anisotropy (CSA), 2H NMR, and C-F rotational echo double resonance (REDOR) experiments. The axis of rotation of 6-F-cholesterol was shown to be in a similar direction to that of cholesterol in DMPC bilayers, which is almost parallel to the long axis of the molecular frame. The molecular order parameter of 6-F-cholesterol was determined to be ca. 0.85, which is within the range of reported values of cholesterol. These findings suggest that the dynamic properties of 6-F-cholesterol in DMPC are quite similar to those of unmodified cholesterol; therefore, the introduction of a fluorine atom at C6 has virtually no effect on cholesterol dynamics in membranes. In addition, this study demonstrates the practical utility of theoretical calculations for determining the 19F CSA principal axes, which would be extremely difficult to obtain experimentally. The combined use of quantum calculations and solid-state 19F NMR will make it possible to apply the orientation information of 19F CSA tensors to membrane systems.

    DOI: 10.1021/ja077580l

  • Effects of lipid constituents on membrane-permeabilizing activity of amphidinols 査読

    Nagy Morsy, Toshihiro Houdai, Keiichi Konoki, Nobuaki Matsumori, Tohru Oishi, Michio Murata

    Bioorganic and Medicinal Chemistry   16 ( 6 )   3084 - 3090   2008年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphidinols (AMs) are a new class of polyhydroxyl polyene compounds with potent antifungal activity. Membrane-permeabilizing activities of AM2, AM3, and AM6 were examined using fluorescent-dye leakage experiments with various phosphatidylcholines (PCs) and sterols. All the AMs tested showed the potent activity to cholesterol-containing liposomes. In the absence of the sterol, AM2, AM3, and AM6 had no membrane-permeabilizing activities to membranes of saturated PC. In liposomes consisting of unsaturated PC, AM2, which possesses an additional ether ring in a polyhydroxyl chain, showed membrane-permeabilizing activities with a moderate efficacy, while AM3 or AM6 did not. The potentiation by sterols was prominent even at 0.5% (wt/wt) and structure-dependent, which ruled out the possibility that alteration of the membrane physical properties induced by sterol was chiefly responsible for this sterol effect. The finding that their activity was not affected by membrane thickness implies that AMs permeabilized membrane by a different mechanism from that of polyene macrolide antibiotics.

    DOI: 10.1016/j.bmc.2007.12.029

  • Self-assembled amphotericin B is probably surrounded by ergosterol Bimolecular interactions as evidenced by solid-state NMR and CD spectra 査読

    Yusuke Kasai, Nobuaki Matsumori, Yuichi Umegawa, Shigeru Matsuoka, Hiroyuki Ueno, Hiroki Ikeuchi, Tohru Oishi, Michio Murata

    Chemistry - A European Journal   14 ( 4 )   1178 - 1185   2008年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B (AmB) is thought to exert its pharmacological effects by forming a barrel-stave assembly with ergosterol in fungal membranes. To examine the interaction between AmB and ergosterol (Erg) or cholesterol (Cho), 13C- and 19F-labelled covalent conjugales were prepared as reported previously (N. Matsumori et al. Chem. Biol. 2004, 11, 673-679). The CD spectra of the conjugates in a membrane-bound form suggested that the distance between the heptaene moieties of the ergosterol conjugates AmB-C 2-(6-F)Erg 2 and AmB-C2Erg 3 is similar to that of AmB in ergosterol-containing membranes, but significantly larger than that of AmB in nonsterol or cholesterol-containing mem branes. These observations suggest that, as is the case with ergosterol-containing membranes, the conjugated sterol moiety prevents the close contact between the heptaene moieties within the membrane that would reduce channel conductivity of the AmB assemblies. To further investigate this bimolecular interaction, we recorded the solid-state NMR spectra of conjugates 2 and AmB-C2-(6-F)Cho 4. which are composed of uniformly 13C-labelled AmB and 6-fluorinuted ergosterol or cholesterol; the conjugates were expected to facilitate the estimation of distances between the fluorine and carbon atoms. By using rotor-synchronous double resonance (rotational echo double resonance of X cluster; RDX) experiments, we deduced the distance between the fluorine atom and its nearest carbon atom in the heptaene moiety of 2 to be less than 8.6 Å. This indicates that the B ring of ergosterol comes close to the AmB polyene moiety. A conformational search of the AmB-ergosterol conjugate by using distance constraints derived from the RDX results suggested that ergosterol molecules possibly surround the AmB assembly, which is in contrast with the conventional image in which ergosterol is inserted into AmB molecules.

    DOI: 10.1002/chem.200701256

  • Conformation and location of membrane-bound salinomycin-sodium complex deduced from NMR in isotropic bicelles 査読

    Nobuaki Matsumori, Atsushi Morooka, Michio Murata

    Journal of the American Chemical Society   129 ( 48 )   14989 - 14995   2007年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    An ionophore antibiotic salinomycin was studied in a membrane environment consisting of isotropic bicelles, a better model for biological membranes than micelles, and its conformation and topological orientation in bicelles was determined. 2D NMR measurements and restrained conformational search revealed that salinomycin-sodium salt in bicelles adopts an open conformation in which the orientation of the E-ring is significantly different from that in crystal and solution structures. This conformational alteration breaks an intramolecular hydrogen bond between 28-OH and 1-O, dislocates the ether oxygen of the E-ring from a coordinated position to the sodium ion observed in the crystal, and consequently weakens the complexation between salinomycin and the sodium ion. Paramagnetic relaxation experiments using doxylphospholipids reveal that salinomycin is embedded shallowly in bicelles, with both terminals being closer to the water interface and the olefin portion facing the bicelle interior. Measurements of intermolecular NOEs between salinomycin and phospholipids further supported this orientation. Weaker complexation with sodium ion and positional preference in the membrane polar region may facilitate the catch-and-release of metal ions at the polar/nonpolar interface of bilayers. On the basis of these findings, a model for salinomycin-assisted transport of metal ions across biological membranes is proposed.

    DOI: 10.1021/ja075024l

  • Amphotericin B covalent dimers with carbonyl-amino linkage a new probe for investigating ion channel assemblies 査読

    Yuichi Umegawa, Nobuaki Matsumori, Tohru Oishi, Michio Murata

    Tetrahedron Letters   48 ( 19 )   3393 - 3396   2007年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Based on an amphotericin B (AmB) ion-channel model where the close proximity of neighboring molecules is effected by interaction between carboxyl and amino groups, we prepared covalent dimers of AmB connected between these functionalities. While directly connected and short-tethered derivatives (2 and 3) lacked the activities, dimer 4 with a longer linker revealed K+ ion flux activity, suggesting that some distance and/or flexibility between the carboxyl and amino groups in adjacent molecules is required for the formation of ion-permeable complex in biomembranes.

    DOI: 10.1016/j.tetlet.2007.03.058

  • Assignment of the absolute configuration of blasticidin A and revision of that of aflastatin A 査読

    Shohei Sakuda, Nobuaki Matsumori, Kazuo Furihata, Hiromichi Nagasawa

    Tetrahedron Letters   48 ( 14 )   2527 - 2531   2007年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The absolute configuration of blasticidin A, a strong inhibitor of aflatoxin production by Aspergillus parasiticus, was assigned by adding the data of relative configurations at its diol and pentaol moieties to previously known stereochemistry. Similarity of the NMR data of blasticidin A to those of aflastatin A allowed us to revise the stereochemistry of the diol and pentaol moieties of aflastatin A.

    DOI: 10.1016/j.tetlet.2007.02.024

  • Conformation and position of membrane-bound amphotericin B deduced from NMR in SDS micelles 査読

    Nobuaki Matsumori, Toshihiro Houdai, Michio Murata

    Journal of Organic Chemistry   72 ( 3 )   700 - 706   2007年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    (Figure Presented) Amphotericin B (AmB) is known to self-assemble to form an ion channel across lipid bilayer membranes. To gain insight into the conformation of AmB in lipidic environments, AmB in SDS micelles was subjected to high-resolution NMR and CD measurements, and the NMR-derived conformation thus obtained was refined by molecular mechanics calculations. These results indicate that AmB in SDS micelles is conformationally fixed particularly for the macrolide moiety. Paramagnetic relaxation experiments with the use of Mn 2+ reveal that AmB is shallowly embedded in the micelle with the polyhydroxyl chain being close to the water interface and the side of polyene portion facing to the micelle interior. CD measurements demonstrate that AmB is in a monomeric form in SDS micelles. The structure of AmB in the micelles obtained in the present study may reproduce the initial stage of membrane interaction of AmB prior to the assembly formation in biomembranes.

    DOI: 10.1021/jo061309p

  • Design and synthesis of an artificial ladder-shaped polyether that interacts with glycophorin A 査読

    Kohei Torikai, Hiroshi Yari, Megumi Mori, Satoru Ujihara, Nobuaki Matsumori, Michio Murata, Tohru Oishi

    Bioorganic and Medicinal Chemistry Letters   16 ( 24 )   6355 - 6359   2006年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ladder-shaped polyether (LSP) compounds, such as brevetoxins and ciguatoxins, are thought to interact with transmembrane (TM) proteins. As a model LSP compound, we designed and synthesized an artificial tetracyclic ether (1) and evaluated its interaction with glycophorin A (GpA), a membrane protein known to dimerize or oligomerize between membrane-integral α-helical domains. Model compound 1 was found to induce the dissociation of oligomeric GpA in a similar manner to natural LSPs when examined by SDS-PAGE. The results suggest that even an artificial tetracyclic ether possesses the ability to interact with TM proteins, presumably through the intermolecular hydrogen bonds (Cα-H ⋯ O) with the GXXXG motif.

    DOI: 10.1016/j.bmcl.2006.09.004

  • Structures of new amphidinols with truncated polyhydroxyl chain and their membrane-permeabilizing activities 査読

    Nagy Morsy, Toshihiro Houdai, Shigeru Matsuoka, Nobuaki Matsumori, Seiji Adachi, Tohru Oishi, Michio Murata, Takashi Iwashita, Tsuyoshi Fujita

    Bioorganic and Medicinal Chemistry   14 ( 19 )   6548 - 6554   2006年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Two new homologues of amphidinols (AM14 and AM15) were isolated from the cultured dinoflagellate Amphidinium klebsii. The structures were elucidated on the basis of 2D NMR and collision-induced dissociation MS/MS and turned out to be closely related homologues of AM7. Their weak membrane-disrupting activity indicates that the hydrophobic polyene chain is essential for the potent biological activities. Structure-activity relationship for the polyhydroxyl part was then examined with use of AM homologues possessing various chain lengths, indicating that the pore size of the channel/lesion formed by AMs was not greatly affected by the length of the polyhydroxyl chain.

    DOI: 10.1016/j.bmc.2006.06.012

  • Membrane interaction of amphotericin B as single-length assembly examined by solid state NMR for uniformly 13C-enriched agent 査読

    Shigeru Matsuoka, Hiroki Ikeuchi, Yuichi Umegawa, Nobuaki Matsumori, Michio Murata

    Bioorganic and Medicinal Chemistry   14 ( 19 )   6608 - 6614   2006年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The membrane interaction of amphotericin B (AmB), one of the most important anti-fungal drugs, was investigated by solid state NMR measurements of uniformly 13C-enriched AmB, which was prepared by the culture of the drug-producing microorganism in the presence of [u-13C6]glucose. All the 13C NMR signals of AmB upon binding to DLPC membrane were successfully assigned on the basis of the 13C-13C correlation spectrum. 13C-31P RDX (Rotational-Echo Double Resonance for X-clusters) experiments clearly revealed the REDOR dephasing effects for carbon atoms residing in the both terminal parts, whereas no dephasing was observed for the middle parts including polyolefinic C20-C33 and hydroxyl-bearing C8/C9 parts. These observations suggest that AmB binds to DLPC membrane with a high affinity to the phospholipid and spans the membrane with a single molecular length.

    DOI: 10.1016/j.bmc.2006.06.001

  • Large molecular assembly of amphotericin B formed in ergosterol-containing membrane evidenced by solid-state NMR of intramolecular bridged derivative 査読

    Nobuaki Matsumori, Yuri Sawada, Michio Murata

    Journal of the American Chemical Society   128 ( 36 )   11977 - 11984   2006年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B (AmB 1) is known to assemble and form an ion channel across biomembranes. We have recently reported that conformation-restricted derivatives of AmB 2-4 show different ergosterol preferences in ion-channel assays, which suggested that the orientation of the mycosamine strongly affects the sterol selectivity of AmB. The data allowed us to assume that compound 3 showing the highest selectivity would reflect the active conformation of AmB in the channel assembly. In this study, to gain further insight into the active conformation of AmB, we prepared a new intramolecular-bridged derivative 5, where the linker encompassed a hydrophilic glycine moiety. The derivative has almost equivalent ion-channel activity to those of AmB and 3. The antifungal activity of 5 compared with 3 improves significantly, possibly because the increasing hydrophilicity in the linker enhances the penetrability through the fungal cell wall. Conformation of 5 was well converged and very similar to that of 3, thus further supporting the notion that the conformations of these derivatives reproduce the active structure of AmB in the channel complex. Then we used the derivative to probe the mobility of AmB in the membrane by solid-state NMR. To measure dipolar couplings and chemical shift anisotropies, we incorporated [1-13C,15N]glycine into the linker. The results indicate that 5 is mostly immobilized in ergosterol-containing DMPC bilayers, implying formation of large aggregates of 5. Meanwhile some fraction of 5 remains mobile in sterol-free DMPC bilayers, suggesting promotion of Amb aggregation by ergosterol.

    DOI: 10.1021/ja063433w

  • Synthesis of 28-19F-amphotericin B methyl ester 査読

    Hiroshi Tsuchikawa, Naohiro Matsushita, Nobuaki Matsumori, Michio Murata, Tohru Oishi

    Tetrahedron Letters   47 ( 35 )   6187 - 6191   2006年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A fluorinated amphotericin B (AmB) derivative, 28-19F-AmB methyl ester (3), labeled at the polyene moiety, was synthesized by combining chemical synthesis with degradation of a natural product via cross-coupling reactions and macrolactonization. The fluorinated derivative 3 showed antifungal activity similar to that of AmB, and is expected to be a powerful tool for NMR-based investigation of the mechanism of ion-channel formation.

    DOI: 10.1016/j.tetlet.2006.06.159

  • Detailed description of the conformation and location of membrane-bound erythromycin A using isotropic bicelles 査読

    Nobuaki Matsumori, Atsushi Morooka, Michio Murata

    Journal of Medicinal Chemistry   49 ( 12 )   3501 - 3508   2006年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although many nonpeptidic drugs target biological membrane and membrane proteins, it is still difficult to define the membrane-bound structure of the drugs. In this study, we utilized bicelles as a membrane model, since the bicelles, which have planar lipid bilayer portions, are thought to be a more appropriate and practical membrane model than micelles. Bicelles with a small diameter allow for measurements of liquid NMR due to fast tumbling in solution. We targeted erythromycin A (EA) as a membrane-binding compound because it is pointed out that the drug interacts with lysosomal membranes, inhibits phospholipase A, and consequently induces phospholipidosis as a side effect. The conformation of EA in the bicelle was successfully determined on the basis of coupling constants and NOEs. Measurements of intermolecular NOEs and paramagnetic relaxation times revealed that the drug is located shallowly in the membrane surface, with the dimethylamino group being close to the phosphate, and the macrolide portion adjacent to upper sides of the acyl chains. This study shows the general utility of isotropic bicelles for detailed conformational and orientational studies of membrane-associated nonpeptidic drugs.

    DOI: 10.1021/jm051210v

  • Derivatization and isotope labeling of amphotericin B aiming at elucidation of the ion-channel structure 査読

    Nobuaki Matsumori, Tohru Oishi, Michio Murata

    Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry   64 ( 5 )   502 - 513   2006年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B (AmB) is known to assemble together and form an ion channel across biomembranes. The selective toxicity is generally accounted for by its higher affinity for ergosterol than cholesterol. To better understand the ion-channel structure and intermolecular interactions, we prepared various AmB derivatives and measured their activities. AmB dimers which are covalently linked between the amino groups by short chains showed more potent ion-channel activity than that of AmB, indicating that the mutual topology of AmB molecules is a head-to-head orientation. AmB-sterol conjugates were also designed and examined for ion-channel activities. AmB-ergosterol conjugates showed more powerful ion-channel activity than AmB-cholesterol congeners, suggesting that stronger van der Waals interaction between AmB and ergosterol contributes to the higher ion-channel activity. Finally, we prepared conformation-restricted derivatives of AmB, in which the amino and carboxyl groups were bridged with various lengths of alkyl chains. The derivatives successfully gave us information on the active-conformation of the sugar moiety of AmB in membrane. These derivatives are now labeled by 13C and/or 19F to probe the molecular structure of AmB ion channel using solid-state NMR.

  • Ladder-shaped polyether compound, desulfated yessotoxin, interacts with membrane-integral α-helix peptides 査読

    Megumi Mori, Tohru Oishi, Shigeru Matsuoka, Satoru Ujihara, Nobuaki Matsumori, Michio Murata, Masayuki Satake, Yasukatsu Oshima, Nobuto Matsushita, Saburo Aimoto

    Bioorganic and Medicinal Chemistry   13 ( 17 )   5099 - 5103   2005年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ladder-shaped polyether compounds, represented by brevetoxins, ciguatoxins, maitotoxin, and prymnesins, are thought to possess the high affinity to transmembrane proteins. As a model compound of ladder-shaped polyethers, we adopted desulfated yessotoxin (2) and examined its interaction with glycopholin A, a membrane protein known to form a dimer or oligomer. Desulfated yessotoxin turned out to interact with the α-helix so as to induce the dissociation of glycopholin oligomers when examined by SDS and PFO gel electrophoresis. The results provided the first evidence that lapper-shaped polyethers interact with transmembrane helix domains.

    DOI: 10.1016/j.bmc.2005.05.039

  • Isolation and structure elucidation of a new amphidinol with a truncated polyhydroxyl chain from Amphidinium klebsii 査読

    Nagy Morsy, Shigeru Matsuoka, Toshihiro Houdai, Nobuaki Matsumori, Seiji Adachi, Michio Murata, Takashi Iwashita, Tsuyoshi Fujita

    Tetrahedron   61 ( 36 )   8606 - 8610   2005年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A new member of amphidinols (AM7) possessing a polyene-polyhydroxyl structure with the shortest carbon backbone and sulfate ester was isolated from the cultured dinoflagellate, Amphidinium klebsii. AM7 showed hemolytic and antifungal activities. The structure was elucidated on the basis of 2D NMR data in combination with CID MS/MS experiments.

    DOI: 10.1016/j.tet.2005.07.004

  • Bioactive fluorinated derivative of amphotericin B 査読

    Nobuaki Matsumori, Yuichi Umegawa, Tohru Oishi, Michio Murata

    Bioorganic and Medicinal Chemistry Letters   15 ( 15 )   3565 - 3567   2005年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The first stably fluorinated derivative of amphotericin B (2) with a fluorine atom in the macrolide skeleton was synthesized using an electrophilic fluorination reagent, Selectfluor®. The derivative 2 showed hemolytic, K+ permeable, and antifungal activities similar to those of AmB and thus was expected to be a powerful tool for NMR-based investigations on the mechanism of ion-channel formation by amphotericin B.

    DOI: 10.1016/j.bmcl.2005.05.058

  • Mycosamine orientation of amphotericin B controlling interaction with ergosterol Sterol-dependent activity of conformation-restricted derivatives with an amino-carbonyl bridge 査読

    Nobuaki Matsumori, Yuri Sawada, Michio Murata

    Journal of the American Chemical Society   127 ( 30 )   10667 - 10675   2005年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B (AmB 1) is known to assemble together and form an ion channel across biomembranes. The antibiotic consists of mycosamine and macrolactone moieties, whose relative geometry is speculated to be determinant for the drug's channel activity and sterol selectivity. To better understand the relationship between the amino-sugar orientation and drug's activity, we prepared conformation-restricted derivatives 2-4, in which the amino and carboxyl groups were bridged together with various lengths of alkyl chains. K+ influx assays across the lipid-bilayer membrane revealed that ergosterol selectivity was markedly different among derivatives; short-bridged derivative 2 almost lost the selectivity, while 3 showed higher ergosterol preference than AmB itself. Monte Carlo conformational analysis of 2-4 based on NOE-derived distances indicated that the amino-sugar moiety of 2 comes close to C41 because of the short bridge, whereas those of 3 and 4 are pointing outward. The mutual orientation of the amino-sugar moiety and macrolide ring is so rigid in derivatives 2 and 3 that these conformations should be unchanged upon complex formation in lipid membranes. These results strongly suggest that the large difference in sterol preference between derivatives 2 and 3 is ascribed to the different orientation of amino-sugar moieties. These findings allowed us to propose a simple model accounting for AmB-sterol interactions, in which hydrogen bonding between 2′-OH of AmB and 3β-OH of ergosterol plays an important role.

    DOI: 10.1021/ja051597r

  • Hairpin conformation of amphidinols possibly accounting for potent membrane permeabilizing activities 査読

    Toshihiro Houdai, Shigeru Matsuoka, Nagy Morsy, Nobuaki Matsumori, Masayuki Satake, Michio Murata

    Tetrahedron   61 ( 11 )   2795 - 2802   2005年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphidinols are a unique dinoflagellate metabolite with potent antifungal activity. We examined membrane permeabilizing action by amphidinol analogues with structural variations in polyhydroxy and polyene moieties. Consequently, the polyene and polyhydroxy moieties turned out to play important roles in binding to lipid bilayer membrane and in forming ion-permeable pore/lesion across membrane, respectively. NMR-constrained modeling experiments have revealed for the fist time that amphidinols in membrane generally take a hairpin configuration, which plausibly accounts for their potent antifungal and other membrane permeabilizing activities.

    DOI: 10.1016/j.tet.2005.01.069

  • Dominant formation of a single-length channel by amphotericin B in dimyristoylphosphatidylcholine membrane evidenced by 13C- 31P rotational echo double resonance 査読

    Shigeru Matsuoka, Hiroki Ikeuchi, Nobuaki Matsumori, Michio Murata

    Biochemistry   44 ( 2 )   704 - 710   2005年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    13C-Labeled amphotericin B (AmB) was prepared by feeding the producing organism Streptomyces nodosus with [3-13C]propionate. The REDOR experiments for dimyristoylphosphatidylcholine (DMPC) membrane using the 13C-labeled AmB showed the prominent dephasing effects between the phosphate group in PC and C41 carboxyl carbon in the polar head. In addition, C39/C40 methyl carbons also gave rise to the significant reduction of their 13C NMR signals, implying that both terminal parts of AmB reside close to the surface of the DMPC membrane. Conversely, the same REDOR experiments with use of distearoylphosphatidylcholine (DSPC) showed no dephasing for the C39/C40 methyl signals while a marked reduction of the C41 carbonyl signal was again observed. These findings should be most reasonably accounted for by the notion that AmB can span across the DMPC membrane with a single-length interaction but cannot span the DSPC membrane due to its greater thickness. To our knowledge, the results provide the first direct spectroscopic evidence for the formation of a single-length channel across a biomembrane, which was previously suggested by channel current recording experiments.

    DOI: 10.1021/bi049001k

  • Amphotericin B covalent dimers bearing a tartarate linkage 査読

    Nobuaki Matsumori, Rie Masuda, Michio Murata

    Chemistry and Biodiversity   1 ( 2 )   346 - 352   2004年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B (AmB, 1) is known to assemble together and form an ion channel across biomembranes, by which the drug presumably exerts its antimicrobial activity. To access the whole architecture of this channel assemblage, the understanding of binary interaction between AmB molecules is of prime importance because the dimeric interaction is the basis of the assemblage. In this context, we have recently reported covalently conjugated AmB dimers such as 2 and 3 with a long linker, which show prominent hemolytic potency and ion-channel activity. To evaluate the effect of the length and hydrophilicity of linker parts on the activity, we prepared new dimers bearing tartarate linkages (4 and 5). Especially, 5 exhibited potent hemolytic activity (EC50, 0.03 μm) surpassing those of AmB, 2, and 3. Measurements of UV and CD spectra of 5 in liposomes indicated that AmB portions of 5 could adopt appropriate arrangements in molecular assemblage in spite of the short linkage, and also indicated that the assemblage formed by 5 appeared more stable than AmB. These short-tethered dimers are expected to be a promising tool to reveal the mechanism of dimeric interaction in the ion channel formed by AmB.

    DOI: 10.1002/cbdv.200490030

  • Membrane-permeabilizing activities of amphidinol 3, polyene-polyhydroxy antifungal from a marine dinoflagellate 査読

    Toshihiro Houdai, Shigeru Matsuoka, Nobuaki Matsumori, Michio Murata

    Biochimica et Biophysica Acta - Biomembranes   1667 ( 1 )   91 - 100   2004年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphidinols, which are polyene-polyhydroxy metabolites produced by the marine dinoflagellate Amphidinium klebsii, possess potent antifungal and hemolytic activities. The membrane permeabilizing actions of amphidinol 3, the most potent homologue, were compared with those of polyene antibiotics, amphotericin B (AmB) and filipin, in hemolytic tests, 23Na nuclear magnetic resonance (NMR)-based membrane permeabilizing assays, and UV spectroscopy for liposome-bound forms. In Na + flux experiments using large unilamellar vesicles (LUVs), ion efflux by amphidinol 3 was inhibited by cholesterol or ergosterol, which was opposed to previous results [J. Mar. Biotechnol., 5 (1997) 124]. When the effect of the agents on the size of vesicles was examined by light scattering experiments, amphidinol 3 did not significantly alter their size while filipin and synthetic detergent Triton X-100 did. The observations implied that the activity of amphidinol 3 was mainly due to formation of large pores/lesions in liposomes rather than detergent-like disruption of membrane. The pore/lesion size was estimated to be 2.0-2.9 nm in diameter on the basis of osmotic protection experiments using blood cells. The UV spectra in liposomes, which revealed the close interaction of polyene moieties in a lipid bilayer, further implied that the membrane activity of amphidinol 3 is caused by the molecular assemblage formed in biomembrane. These results disclose that amphidinol 3 is one of few non-ionic compounds that possess potent membrane permeabilizing activity with non-detergent mechanism.

    DOI: 10.1016/j.bbamem.2004.09.002

  • Synthesis and conformation of deuterated spermidine for investigating weak interaction with polyanionic biomolecules 査読

    Keisuke Maruyoshi, Tetsuo Demura, Takeshi Sagane, Nobuaki Matsumori, Tohru Oishi, Michio Murata

    Tetrahedron   60 ( 24 )   5163 - 5170   2004年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Polyamines such as spermidine and spermine are known to interact with polyanionic biomolecules under physiological conditions. Conformation analysis of these highly flexible acycles is virtually unprecedented due to the lack of appropriate methodologies. Spin-spin coupling constants, which are often utilized for acyclic systems, are rather uninformative for polyamines due to unresolved 1H NMR signals of their tri- and tetra-methylene moieties. We attempted to solve this problem by synthesizing diastereospecifically deuterated spermidine, (1S*,2S*)-1,8-diamino- 4-azaoctane-1,2,3,3,5,5,6,6,7,7,8,8-d12. To evaluate its utility, 1H-1H spin coupling constants were measured as trihydrochloride or tripolyphosphate salt. The relevant coupling constant markedly decreased upon complexation to tripolyphosphate. Under neutral pH, where the net charge of tripolyphosphate became tetravalent, the coupling constant was small; as pH was lowered to 1.4, where the charge was divalent, the constant increased significantly. These data clearly indicate that, when interacting with polyanions, spermidine undergoes conformational changes to increase bent conformation, which could be effectively monitored by the deuterated spermidine.

    DOI: 10.1016/j.tet.2004.04.056

  • An amphotericin B-ergosterol covalent conjugate with powerful membrane permeabilizing activity 査読

    Nobuaki Matsumori, Noritsugu Eiraku, Shigeru Matsuoka, Tohru Oishi, Michio Murata, Takaaki Aoki, Toru Ide

    Chemistry and Biology   11 ( 5 )   673 - 679   2004年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amphotericin B-sterol conjugates were synthesized and examined for their membrane permeabilizing activity. Ergosterol and cholesterol, each connected with amphotericin B via an ethylenecarbamate or hexamethylenecarbamate linker, were examined by K+ flux assays using liposomes and by single-channel recording across phospholipid membrane. Among four conjugates tested, AmB-ergosterol bearing an ethylenecarbamate linker exhibited the most powerful activity, which substantially exceeded that of the cholesterol homolog. Single-channel recording clearly exhibited that the ergosterol conjugate elicited channel current with the conductance of 28 pS, which was comparable with those by AmB, and revealed a higher channel open probability than the cholesterol conjugate. These results imply that direct interaction between amphotericin B and ergosterol is reproduced by their conjugate, which may serve as a model compound for understanding the drug's selective toxicity.

    DOI: 10.1016/j.chembiol.2004.02.027

  • Amphotericin B-phospholipid covalent conjugates Dependence of membrane-permeabilizing activity on acyl-chain length 査読

    Shigeru Matsuoka, Nobuaki Matsumori, Michio Murata

    Organic and Biomolecular Chemistry   1 ( 22 )   3882 - 3884   2003年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The interaction between amphotericin B and phospholipid upon forming ion channels across a biomembrane was investigated using their covalent conjugates. The membrane permeabilizing activity was greatly affected by the chain length of the fatty acyl groups, suggesting that their interaction is involved in ion channel assemblages.

    DOI: 10.1039/b306801c

  • Amphotericin B Dimers with Bisamide Linkage Bearing Powerful Membrane-Permeabilizing Activity 査読

    Nahoko Yamaji, Nobuaki Matsumori, Shigeru Matsuoka, Tohru Oishi, Michio Murata

    Organic Letters   4 ( 12 )   2087 - 2089   2002年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    (Matrix Presented) Covalently linked dimers of amphotericin B were prepared by cross-linking its carboxylic acid. Among these, a dimer with a linkage of 1,6-hexanediamine revealed potent hemolytic activity (EC50,0.25 μM) while its N-acetyl derivative gave rise to large K+ ion flux in phosphatidylcholine liposomes, regardless of the presence or absence of sterols, suggesting that the dimers may serve as a tool for elucidating the structure of the ion channel assemblage formed by amphotericin B.

    DOI: 10.1021/ol025982m

  • Amphotericin B covalent dimers forming sterol-dependent ion-permeable membrane channels 査読

    Nobuaki Matsumori, Nahoko Yamaji, Shigeru Matsuoka, Tohru Oishi, Michio Murata

    Journal of the American Chemical Society   124 ( 16 )   4180 - 4181   2002年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Polyenemacrolides such as amphotericin B (AmB) were thought to assemble together and form an ion channel across plasma membranes. Their antimicrobial activity has been accounted for by this assemblage, whose stability and activity are dependent on sterol constituents of lipid bilayer membranes. The structure of this channel-like assemblage formed in biomembranes has been a target of extensive investigations for a long time. For the first step to this goal, we prepared several AmB dimers with various linkers and tested for their channel-forming activity. Among these, AmB dimers that bore an aminoalkyl-dicarboxylate tether covalently linked between amino groups of AmB showed potent hemolytic activity. Furthermore, K+ influx actions monitored by measuring the pH of the liposome lumen by 31P NMR revealed that the dimers formed the molecular assemblage similar to that of AmB in phospholipid membrane. Judging from changes in 31P NMR spectra, the dimers appeared to induce "all-or-none"-type ion flux across the liposome membrane in the presence of ergosterol, which suggested that the ion channel formed by ergosterol/dimer is similar to that of AmB. With these data in hand, we are now trying to elucidate the structure of the ion-channel complex by making the labeled conjugates of AmB for NMR measurements.

    DOI: 10.1021/ja012026b

  • Absolute configuration of aflastatin A, a specific inhibitor of aflatoxin production by Aspergillus parasiticus 査読

    Hiroyuki Ikeda, Nobuaki Matsumori, Makoto Ono, Akinori Suzuki, Akira Isogai, Hiromichi Nagasawa, Shohei Sakuda

    Journal of Organic Chemistry   65 ( 2 )   438 - 444   2000年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Aflastatin A (1) is a specific inhibitor of aflatoxin production by Aspergillus parasiticus. It has the novel structure of a tetramic acid derivative with a long alkyl side chain. The absolute configurations of 29 chiral centers contained in I were chemically elucidated in this study. First, four small fragment molecules were prepared from I or its methyl ether (2), and their absolute structures were assigned as N-methyl-D-alanine, (2S,4R)-2,4-dimethyl-1,6-hexanediol dibenzoate, (R)-3-hydroxydodecanoic acid, and (R)-1,2,4-butanetriol tribenzoate. Next, an acyclic fragment molecule 3 with 13 chiral centers was obtained from I by NaIO4 oxidation, and its relative stereochemistry was elucidated by J-based configuration analysis. By analyzing coupling constants of 3J(H,H) and 2,3J(C,H) and ROE data, the relative configuration of 3 was verified. Finally, by further J-based configuration analysis using a fragment molecule 7 prepared from 2 with 28 chiral carbons, all relative configurations in the alkyl side chain of I were clarified. By connecting these relative configurations with the absolute configurations of first four fragment molecules, the absolute stereochemistry of 1 was fully determined.

    DOI: 10.1021/jo991284c

  • Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region 査読

    Nobuaki Kudo, Nobuaki Matsumori, Hiroshi Taoka, Daisuke Fujiwara, Erwin P. Schreiner, Barbara Wolff, Minoru Yoshida, Sueharu Horinouchi

    Proceedings of the National Academy of Sciences of the United States of America   96 ( 16 )   9112 - 9117   1999年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The cellular target of leptomycin B (LMB), a nuclear export inhibitor, has been identified as CRM1 (exportin 1), an evolutionarily conserved receptor for the nuclear export signal of proteins. However, the mechanism by which LMB inhibits CRM1 still remains unclear. CRM1 in a Schizo-saccharomyces pombe mutant showing extremely high resistance to LMB had a single amino acid replacement at Cys-529 with Ser. The mutant gene, named crm1-K1, conferred LMB resistance on wild-type S. pombe, and Crm1-K1 no longer bound biotinylated LMB. 1H NMR analysis showed that LMB bound N-acetyl-L-cysteine methyl ester through a Michael-type addition, consistent with the idea that LMB binds covalently via its α,β-unsaturated δ-lactone to the sulfhydryl group of Cys-529. When HeLa cells were cultured with biotinylated LMB, the only cellular protein bound covalently was CRM1. Inhibition by N- ethylmaleimide (NEM), an alkylating agent, of CRM1-mediated nuclear export probably was caused by covalent binding of the electrophilic structure in NEM to the sulfhydryl group of Cys-529, because the crm1-K1 mutant showed the normal rate for the export of Rev nuclear export signal-bearing proteins in the presence of not only LMB but also NEM. These results show that the single cysteine residue determines LMB sensitivity and is selectively alkylated by LMB, leading to CRM1 inactivation.

    DOI: 10.1073/pnas.96.16.9112

  • Absolute configuration of amphidinol 3, the first complete structure determination from amphidinol homologues Application of a new configuration analysis based on carbon-hydrogen spin-coupling constants [8] 査読

    Michio Murata, Shigeru Matsuoka, Nobuaki Matsumori, Gopal K. Paul, Kazuo Tachibana

    Journal of the American Chemical Society   121 ( 4 )   870 - 871   1999年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1021/ja983655x

  • Stereochemical determination of acyclic structures based on carbon- proton spin-coupling constants. A method of configuration analysis for natural products 査読

    Nobuaki Matsumori, Daisuke Kaneno, Michio Murata, Hideshi Nakamura, Kazuo Tachibana

    Journal of Organic Chemistry   64 ( 3 )   866 - 876   1999年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A method for elucidating the relative configuration of acyclic organic compounds was developed on the basis of carbon-proton spin-coupling constants (2,3J(C,H)) and interproton spin-coupling constants (3J(H,H)). This method is based on the theory that, in acyclic systems, the conformation of adjacent asymmetric centers is represented by staggered rotamers, and their relative stereochemistry can be determined using 2,3J(C,H) and 3J(H,H), because the combined use of these J values enables the identification of the predominant staggered rotamer(s) out of the six possible derived from threo and erythro configurations. Detailed conformational analysis for model compounds 1-4 revealed that this method is useful in most cases for assignment of the configuration of acyclic structures occurring in natural products, in which stereogenic methine carbons are often substituted with a methyl or a hydroxy (alkoxy) group. This J-based configuration analysis was applied to the stereochemical elucidation of carboxylic acid 5 derived from zooxanthellatoxin and proven to be a practical method even for natural products with complicated structures.

    DOI: 10.1021/jo981810k

  • Absolute structure and total synthesis of lipogrammistin-A, a lipophilic ichthyotoxin of the soapfish 査読

    Hiroyuki Onuki, Kei Ito, Yoshimasa Kobayashi, Nobuaki Matsumori, Kazuo Tachibana, Nobuhiro Fusetani

    Journal of Organic Chemistry   63 ( 12 )   3925 - 3932   1998年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Lipogrammistin-A (1b) was isolated as an ichthyotoxic and hemolytic constituent of the skin mucus of the grammistid fish Aulacocephalus temmincki. Its absolute stereochemistry was established by chemical degradation and total synthesis. The stereochemistry of the 2-methylbutyryl moieties attached to N9 and N15 was determined to be S by HPLC analysis of a diastereomeric derivative. The stereochemistry of the remaining C4 position was elucidated to be S by a total synthesis of the two diastereomers (4S)- and (4R)-1.

    DOI: 10.1021/jo9722461

  • Analysis of relative configuration of acyclic compounds based on long-range carbon-proton coupling constants determined by two dimensional NMR 査読

    Michio Murata, Nobuaki Matsumori, Kazuo Tachibana

    Unknown Journal   ( 11 )   749 - 757   1997年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A new NMR methodology was devised for configurational assignments of acyclic structures in natural products or synthetic compounds. Conventional methods based on NOEs often suffer from the ambiguity in assigning the configurations of compounds with acyclic structures and conformational alternation. Unlike these NOE analyses, the new methodology is based on the dihedral angle dependency of long-range carbon-proton coupling constants (2,3JC.H). The combination of the coupling constants (2,3JC.H, 3JH,H) which are categorized to large, medium, or small allows to determine the relative stereochemistry among adjacent asymmetric centers or those separated by a methylene group. Hetero half-filter TOCSY (HETLOC) was shown to be the most effective for measuring 2,3JC,H of protonated carbon system. For structures with quaternary carbons or weakly coupling protons, in which TOCSY in HETLOC fails to correlate relevant protons, phase-sensitive HMBC (HMQC optimized for long-range coupling) worked effectively. To evaluate the utility of the method in structural analysis of natural products, the relative configurations of acyclic portions of maitotoxin, the largest secondary metabolite known to date, were assigned by this method, which evidently demonstrated the validity of 2,3JC,H in the configurational and conformational analysis of organic compounds.

    DOI: 10.1246/nikkashi.1997.749

  • Involvement of AfsA in A-factor biosynthesis as a key enzyme 査読

    Noriko Ando, Nobuaki Matsumori, Shohei Sakuda, Teruhiko Beppu, Sueharu Horinouchi

    Journal of Antibiotics   50 ( 10 )   847 - 852   1997年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The afsA gene of Streptomyces griseus has been postulated to encode a key enzyme for A-factor biosynthesis from primary metabolites commonly present in Streptomyces strains. Escherichia coli cells harboring afsA under the control of the T7 promoter specified distinct A-factor activity in the culture broth, as determined by induction of streptomycin production and aerial mycelium and spore formation in an A-factor-deficient S. griseus mutant strain. Production of the substance(s) having A-factor activity was inhibited by cerulenin, an inhibitor of fatty acid biosynthesis. These observations suggest that afsA encodes a key enzyme in the A-factor biosynthetic pathway in which a β-keto acid derived from fatty acid biosynthesis and a glycerol derivative serve as precursors.

    DOI: 10.7164/antibiotics.50.847

  • Chemical structures of amphidinols 5 and 6 isolated from marine dinoflagellate Amphidinium klebsii and their cholesterol-dependent membrane disruption 査読

    Gopal K. Paul, Nobuaki Matsumori, Keiichi Konoki, Michio Murata, Kazuo Tachibana

    Journal of Marine Biotechnology   5 ( 2-3 )   124 - 128   1997年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A series of polyhydroxy-polyene compounds were isolated from the cultured dinoflagellate Amphidinium klebsii as well as from its surrounding media. Amphidinol 5 (AM 5) and 6 (AM 6) were found to be potent antifungal and hemolytic agents. Their permeabilizing activity towards phospholipid liposomes was markedly enhanced by the presence of cholesterol within the bilayer, indicating that the mechanism of action involved interaction with membranal cholesterol.

  • Long-range carbon-proton coupling constants for stereochemical assignment of acyclic structures in natural products Configuration of the C5-C9 portion of maitotoxin 査読

    Nobuaki Matsumori, Taro Nonomura, Makoto Sasaki, Michio Murata, Kazuo Tachibana, Masayuki Satake, Takeshi Yasumoto

    Tetrahedron Letters   37 ( 8 )   1269 - 1272   1996年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Long-range carbon-proton coupling constants (2,3J(C,H)) were measured for maitotoxin (MTX), one of the largest natural non-biopolymers, by hetero-half filter experiments and phase-sensitive HMBC with use of 9 mg of a 4% 13C-enriched sample. The necessary coupling constants within the terminal acyclic portions of MTX, where NOE analysis was not successful owing to the presumed coexistence of multiple conformers, were thus obtained for the resultant elucidation of relative configurations for the acyclic stereogenic centers to the 5R*, 7R*, 8R*, and 9S*.

    DOI: 10.1016/0040-4039(95)02413-1

  • The Complete Structure of Maitotoxin, Part II Configuration of the C135-C142 Side Chain and Absolute Configuration of the Entire Molecule 査読

    Taro Nonomura, Makoto Sasaki, Nobuaki Matsumori, Michio Murata, Kazuo Tachibana, Takeshi Yasumoto

    Angewandte Chemie (International Edition in English)   35 ( 15 )   1675 - 1678   1996年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/anie.199616751

  • The Complete Structure of Maitotoxin, Part I Configuration of the C1-C14 Side Chain 査読

    Makoto Sasaki, Nobuaki Matsumori, Takahiro Maruyama, Taro Nonomura, Michio Murata, Kazuo Tachibana, Takeshi Yasumoto

    Angewandte Chemie (International Edition in English)   35 ( 15 )   1672 - 1675   1996年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/anie.199616721

  • Stereochemical assignment of the C35-C39 Acyclic linkage in maitotoxin completion of stereochemical determination of C15-C134 査読

    Makoto Sasaki, Nobuaki Matsumori, Michio Murata, Kazuo Tachibana, Takeshi Yasumoto

    Tetrahedron Letters   36 ( 49 )   9011 - 9014   1995年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The relative configuration of carbons within the C35-C39 acyclic linkage of maitotoxin (MTX) was assigned by synthesis of stereodefined model compound 1 and its comparison with MTX in 1H and 13C NMR spectra. This result completed Stereochemical assignments of the whole molecule except for side chains.

    DOI: 10.1016/0040-4039(95)01973-L

  • Conformational analysis of natural products using long-range carbon-proton coupling constants Three-dimensional structure of okadaic acid in solution 査読

    Nobuaki Matsumori, Michio Murata, Kazuo Tachibana

    Tetrahedron   51 ( 45 )   12229 - 12238   1995年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Long-range carbon-proton coupling constants (2,3JC,H) are known to depend on the dihedral angles as is the well-known case with interproton couplings. The precise measurement of these J values were carried out using hetero half-filtered TOCSY and phase-sensitive HMBC on a marine natural product, okadaic acid. From the obtained values together with 3JH,H we disclosed the conformations of okadaic acid in organic and aqueous solutions (CD3OD-CDCl3 or NaOD/D2O), which resembled each other and that obtained for its crystalline o-bromobenzyl ester. The successful result in the present conformational study, even though as an exmaple, demonstrated this methodology to be powerful in elucidation of conformations and configurations of acyclic or macrocyclic portions in natural products of this size.

    DOI: 10.1016/0040-4020(95)00790-F

  • Isolation and chemical structure of amphidinol 2, a potent hemolytic compound from marine dinoflagellate Amphidinium klebsii 査読

    Gopal K. Paul, Nobuaki Matsumori, Michio Murata, Kazuo Tachibana

    Tetrahedron Letters   36 ( 35 )   6279 - 6282   1995年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A new polyene-polyhydroxy compound, amphidinol 2 (2), was isolated as a potent hemolytic and antifungal agent from a cultured strain of dinoflagellate Amphidinium klebsii. The structure elucidated by spectroscopic methods turned out to be partly analogous to amphidinol 1 (1), which had been reported from the different strain of A. klebsii.

    DOI: 10.1016/0040-4039(95)01259-K

▼全件表示

書籍等出版物

  • 天然物の化学Ⅱ(科学のとびら64)

    松森信明, 村田道雄(担当:共著)

    2018年5月 

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    担当ページ:第24章 エリスロマイシンと膜脂質   記述言語:日本語   著書種別:一般書・啓蒙書

  • Experimental Approaches of NMR Spectroscopy

    Nobuaki Matsumori, Michio Murata(担当:共著)

    Springer, Singapore  2018年3月 

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    担当ページ:383-414   記述言語:英語   著書種別:学術書

    In this chapter we overview two topics on NMR methodologies for small molecules, mostly natural products; one is about the solution NMR-based methods used for stereochemical determination of natural products, and the other is on the solid-state and other techniques for investigating natural product-membrane interactions. Since important two methods for stereochemical analysis of natural products, namely the J-based configuration analysis (JBCA) and universal NMR database (UDB) methods, were reported in the 1990s, both methods have been widely used in the field of natural products. The newly coming RDC method is not the major method in the field of natural products yet, but will surely be an important tool for the stereochemical correlation between distant stereogenic centers, which could provide invaluable information as to the whole shape of natural products in solution. In the latter part of this chapter, we discuss the application of solid-state and other NMR techniques to membrane interaction analysis of natural products. In particular, we describe three examples of natural products that interact with biological membranes such as amphotericin B, erythromycin A, and theonellamide A. As shown in NMR studies of amphotericin B, natural products often reveal very high affinities for phospholipids and sterols in bilayer membranes. Solid-state NMR, therefore, provides a very promising approach toward the structure study of membrane-active complexes formed by natural products that have high affinity to lipids. In addition, solution NMR techniques can be applied to elucidate the structural features of membrane-bound small molecules such as antibiotic erythromycin A and membrane-disrupting cyclic peptide theonellamide A. Standard 2D 1H–1H experiments such as COSY (correlation spectroscopy), NOESY (nuclear Overhauser effect spectroscopy), and DOSY (diffusion-ordered spectroscopy) are often helpful in elucidating the membrane interaction between natural products and lipids.

  • Annual Reports on NMR Spectroscopy Vol 94 Chapter 2

    Yuichi Umegawa, Nobuaki Matsumori, Michio Murata(担当:共著)

    Academic Press  2018年1月 

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    担当ページ:Vol 94, Chapter 2 Chapter Two - Recent Solid-State NMR Studies of Hydrated Lipid Membranes, page 41-72   記述言語:英語   著書種別:学術書

    Interactional and structural analyses of lipids in hydrated biomembranes are at the frontier of membrane physics and biology. Recently, solid-state NMR has emerged as a frequently used technique for the investigation of biomembrane systems, leading to particularly remarkable advances in the study of the structural biology of membrane proteins. However, conformational and interactional analyses of lipid molecules and membrane-active small compounds remain challenging. This chapter highlights recent applications of solid-state NMR to membrane lipids and nonpeptidic molecules such as membrane-active natural products. Lipid rafts are microdomains in cellular membranes formed by sphingomyelin and cholesterol and are thought to constitute a platform for signal transduction. Amphotericin B, theonellamide-A, and amphidinol 3 exert their activities by interacting with lipid membranes. Deuterium quadrupole coupling combined with dipole–dipole interactions has been used to evaluate the interaction modes and dynamic properties of membrane lipids and small membrane-active compounds. Herein, we review the recent advances in these topics using our recent research studies as examples of solid-state NMR investigations of hydrated lipid bilayers.

    DOI: doi.org/10.1016/bs.arnmr.2017.12.003

  • タンパク質結晶の最前線

    松森 信明(担当:共著)

    シーエムシー出版  2013年12月 

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    記述言語:日本語   著書種別:学術書

  • ソレル有機化学 上

    松森信明(担当:共訳)

    東京化学同人  2009年3月 

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    担当ページ:13章 1H NMRおよび13C NMR分光法   記述言語:日本語   著書種別:学術書

講演・口頭発表等

  • Small molecule interactions with membrane sterol 招待 国際会議

    松森 信明

    Pacifichem2015  2015年12月 

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    開催年月日: 2015年12月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:Honolulu   国名:アメリカ合衆国  

  • NMR studies of lipid rafts 招待 国際会議

    松森 信明

    Pacifichem2015  2015年12月 

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    開催年月日: 2015年12月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:Honolulu   国名:アメリカ合衆国  

  • NMRによる生体膜ならびに膜作用生理活性物質の解析 招待

    松森 信明

    日本生化学会大会  2014年10月 

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    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(公募)  

    開催地:京都   国名:日本国  

    多数の薬物は膜タンパク質や脂質膜を標的としており、また近年では脂質ラフトと呼ばれる生体膜中の微小領域がシグナル伝達など重要な生理機能を担っていることが明らかとなるなど、脂質膜の詳細な解析の必要性が高まっている。我々はこれまで、有機合成とNMRを組み合わせて膜中における相互作用解析や構造解析を行ってきた。本講演では、バイセル、アンフォテリシンB (AmB)および脂質ラフトについて、我々の最近の研究を紹介する。 バイセル バイセルは長鎖リン脂質と界面活性剤から構成される脂質複合体で、二重膜構造を有することから、ミセルよりもすぐれた膜モデルと考えられている。我々は、このバイセルに有機分子を含有させ、溶液NMRによる配座解析や膜中での存在位置決定を行ってきた1)。この方法論の確立により、イオノフォア抗生物質サリノマイシンのイオン輸送メカニズムの解析などを行ってきた2)。 アンフォテリシンB 真菌感染症治療に用いられるアンフォテリシンB(AmB)は、細胞膜のイオン透過性を昂進させることで抗真菌活性を発揮する。その選択毒性は、コレステロールよりも真菌細胞膜含有のエルゴステロールに対する高い親和性に起因する。しかし、脂質膜中におけるAmBとエルゴステロールの相互作用を直接観測した研究はまだない。そこで本研究ではまず2H標識したステロールを調製し、2H NMRによって脂質膜中での運動性を評価した。その結果、エルゴステロールの膜中での運動性はAmBとの共存によって顕著に低下するのに対し、コレステロールのそれは変化しなかった3)。これは膜中でのAmBとエルゴステロールの相互作用を直接示した最初の研究である。次にフッ素化AmBおよび13C標識エルゴステロールを用い、膜中で19Fと13Cの原子間距離を測定した。その結果、エルゴステロールとAmBが平行に相互作用した状態ばかりでなく、逆平行でも相互作用することが明らかとなった4)。 脂質ラフト 脂質ラフトはスフィンゴミエリン(SM)およびコレステロールを主成分とする細胞膜ドメインであり、特異的に集積した膜タンパク質を介したシグナル伝達のプラットホームとして機能していると考えられている。しかし、脂質ラフトは形成と離散を繰り返しているため、分子レベルでの相互作用解析はほとんど行われていない。本研究では、まず上述のバイセルをSMで調製し、SMの膜中での配座の決定に成功した5)。さらに位置特異的に重水素標識したSMを合成し、2H-NMR 測定からSMの動的挙動を詳細に解析するとともに6,7)、 13C及び15Nで標識したSMを調製し、固体NMR法による配向解析や分子間水素結合の観測を行った。これらの結果から、脂質ラフト形成の分子機構について考察する。 上記以外にも、蛍光顕微鏡を用いた脂質膜の観測や、脂質を固定化したビーズによる脂質結合タンパク質のスクリーニングを行っている。このように、膜タンパク質を含む生体膜における構造解析や相互作用解明に対して、NMRをはじめとした種々の分析手法を用いて多角的なアプローチを展開している。

  • 潜在空間を構成・検証する生物活性の時空間定量計測手法開発・応用 招待

    松森信明

    日本化学会第104春季年会  2024年3月 

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    開催年月日: 2024年3月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:千葉県船橋市   国名:日本国  

  • Ladder-shaped polycyclic ether desulfo-yessotoxin strongly inhibits vacuolar-type ATPase 招待 国際会議

    Nobuaki Matsumori

    ICPAC-Bali 2023  2023年9月 

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    開催年月日: 2023年9月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:bali   国名:日本国  

  • 脂質機能解明のための多角的分析 招待

    松森信明

    脂質駆動学術産業創生研究部会  2022年12月 

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    開催年月日: 2022年12月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:九州大学   国名:日本国  

  • Interaction Analysis between Membrane Proteins and Lipids 招待 国際会議

    Nobuaki Matsumori

    ICPAC Kotakinabalu 2022  2022年11月 

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    開催年月日: 2022年11月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:Kotakinabalu   国名:マレーシア  

  • 脂質と膜タンパク質の相互作用解析法の開発とその応用 招待

    松森信明

    公益財団法人山田科学振興財団 2022年度研究交歓会  2022年10月 

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    開催年月日: 2022年10月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:品川   国名:日本国  

  • Interaction analysis between membrane proteins and lipids towards elucidation of lipid-related chemical communications 国際会議

    Nobuaki Matsumori

    Pacifichem2021  2021年12月 

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    開催年月日: 2021年12月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:オンライン   国名:アメリカ合衆国  

  • 脂質ラフトと麻酔作用 招待

    松森信明

    麻酔メカニズム研究会  2021年12月 

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    開催年月日: 2021年12月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    開催地:オンライン   国名:日本国  

  • Interaction analysis between membrane proteins and lipids to understand biological membranes 招待

    Nobuaki Matsumori

    The 59th Japanese Biophysical Society Meeting  2021年11月 

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    開催年月日: 2021年11月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:オンライン   国名:日本国  

  • 脂質-膜タンパク質相互作用解析法の開発とその応用 招待

    松森信明

    新学術領域研究「化学コミュニケーションのフロンティア」第8回公開シンポジウム  2021年7月 

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    開催年月日: 2021年7月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:オンライン   国名:日本国  

  • 局所麻酔の新たなメカニズム 招待

    松森信明

    ペインクリニック学会第54回学術集会  2020年11月 

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    開催年月日: 2020年11月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:オンライン   国名:日本国  

  • 脂質膜における各種相互作用の解析 招待

    松森信明

    生体膜を含む生体分子間相互作用研究の現状と課題  2019年8月 

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    開催年月日: 2019年8月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:高知大学朝倉キャンパス   国名:日本国  

  • Development of novel fluorescent analogs of sphingomyelins, ceramide, and hybrid phosphatidylcholines. 国際会議

    Takaaki Matsufuji, Kana Hirano, Yutaro Tajima, Masanao Kinoshita, and Nobuaki Matsumori

    The International Conference on the Bioscience of Lipids (ICBL)  2019年6月 

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    開催年月日: 2019年6月

    記述言語:英語  

    開催地:Tokyo   国名:日本国  

  • 膜タンパク質―脂質相互作用解析法の開発:脂質ケミカルバイオロジー創成に向けて

    #稲田壮峰、木下祥尚、松森信明

    日本ケミカルバイオロジー学会 第14回年会  2019年6月 

     詳細を見る

    開催年月日: 2019年6月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:名古屋   国名:日本国  

  • Integrated Analysis of Membrane Systems 招待 国際会議

    Nobuaki Matsumori

    International Seminar on Biophysics and Chemical Biology of Biomembrane and Lipid Bilayers  2017年10月 

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    開催年月日: 2017年10月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:大阪大学豊中キャンパス   国名:日本国  

  • NMR and Fluorescent Studies of Lipid Rafts 招待 国際会議

    Nobuaki Matsumori, Masanao Kinoshita

    9th Korea-Japan Seminars on Biomolecular Sciences: Experimental and Simulations  2016年11月 

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    開催年月日: 2016年11月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:慶州市   国名:大韓民国  

  • 脂質膜における動的挙動、構造および相互作用解析 招待

    松森 信明

    蛋白研セミナー Mechanism of Biology of Membrane: 生体膜上の生物化学  2016年3月 

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    開催年月日: 2016年3月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:吹田市   国名:日本国  

  • 脂質ラフト形成基盤の解明を目指したスフィンゴミエリンの動的およびNMR構造解析 招待

    松森 信明

    日本化学会第96春季年会、ケミカルバイオロジーの新機軸ー機器分析とライフイノベーション  2016年3月 

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    開催年月日: 2016年3月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:京田辺   国名:日本国  

  • 脂質ラフトにおける脂質分子の動的挙動および構造解析 招待

    松森 信明

    第88回日本生化学会大会フォーラム  2015年12月 

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    開催年月日: 2015年12月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:神戸市   国名:日本国  

  • 脂質膜の統合分析 招待

    松森 信明

    第33回九州コロイドコロキウム  2015年11月 

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    開催年月日: 2015年11月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    開催地:福岡市   国名:日本国  

  • 脂質ラフトのNMR解析 招待

    松森 信明

    第53回日本生物物理学会年会  2015年9月 

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    開催年月日: 2015年9月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:金沢大学   国名:日本国  

  • 生体膜の統合分析を目指して 招待

    松森 信明

    統合分析・生物化学研究特区公開講演会  2015年3月 

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    開催年月日: 2015年3月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:九州大学   国名:日本国  

  • 脳分子解析のための超高感度キャピラリー電気泳動-質量分析法の開発と応用

    猪狩 世玲菜, 劉 晨晨, 木下 祥尚, 松森 信明, 淺野 紘史, 宮田 茂雄, 上田 修平, 竹本 さやか, 川井 隆之

    日本分析化学会講演要旨集  2022年9月  (公社)日本分析化学会

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    記述言語:日本語  

  • 神経芽腫細胞を用いた局所麻酔薬による脂質ラフトの形成抑制(Local anesthetics suppress the formation of lipid rafts in mouse neuroblastoma(Neuro2a) cell membranes)

    Nishimura Aoi, Tanaka Yasuhiro, Kinoshita Masanao, Torikai Kohei, Kawai Takayuki, Matsumori Nobuaki

    生物物理  2023年10月  (一社)日本生物物理学会

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    記述言語:英語  

  • 生体膜マイクロドメインを標的とした微量脂質分析法の開発

    久保田 颯, 伊藤 美由紀, 今田 皇緑, 劉 晨晨, 木下 祥尚, 松森 信明, 川井 隆之

    日本分析化学会講演要旨集  2022年9月  (公社)日本分析化学会

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    記述言語:日本語  

  • 液体クロマトグラフィー/キャピラリー電気泳動二次元糖鎖解析法の開発

    三木 太陽, 劉 晨晨, 木下 祥尚, 松森 信明, 山本 佐知雄, 木下 充弘, 川井 隆之

    日本分析化学会講演要旨集  2022年9月  (公社)日本分析化学会

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    記述言語:日本語  

  • 脳分子解析のための超高感度キャピラリー電気泳動-質量分析法の開発と応用

    猪狩 世玲菜, 劉 晨晨, 木下 祥尚, 松森 信明, 淺野 紘史, 宮田 茂雄, 上田 修平, 竹本 さやか, 川井 隆之

    日本分析化学会講演要旨集  2022年9月  (公社)日本分析化学会

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    記述言語:日本語  

  • 細胞破裂に基づく簡便な生体膜透過性評価法

    猪狩 世玲菜, 劉 晨晨, 鳥飼 浩平, 木下 祥尚, 松森 信明, 川井 隆之

    日本分析化学会講演要旨集  2023年9月  (公社)日本分析化学会

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    記述言語:日本語  

  • 糖脂質糖鎖を対象とした超高感度キャピラリー電気泳動分析法の開発

    何 甦恩, 三木 太陽, 劉 晨晨, 木下 祥尚, 松森 信明, 川井 隆之

    日本分析化学会講演要旨集  2023年9月  (公社)日本分析化学会

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    記述言語:日本語  

  • 神経芽腫細胞を用いた局所麻酔薬による脂質ラフトの形成抑制(Local anesthetics suppress the formation of lipid rafts in mouse neuroblastoma(Neuro2a) cell membranes)

    Nishimura Aoi, Tanaka Yasuhiro, Kinoshita Masanao, Torikai Kohei, Kawai Takayuki, Matsumori Nobuaki

    生物物理  2023年10月  (一社)日本生物物理学会

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    記述言語:英語  

  • 生体膜局所の定量的脂質プロファイリングに向けたマイクロニードル固相抽出 質量分析法の開発

    久保田 颯, 伊藤 美由紀, 劉 晨晨, 鳥飼 浩平, 木下 祥尚, 松森 信明, 川井 隆之

    日本分析化学会講演要旨集  2023年9月  (公社)日本分析化学会

     詳細を見る

    記述言語:日本語  

  • 生体膜マイクロドメインを標的とした微量脂質分析法の開発

    久保田 颯, 伊藤 美由紀, 今田 皇緑, 劉 晨晨, 木下 祥尚, 松森 信明, 川井 隆之

    日本分析化学会講演要旨集  2022年9月  (公社)日本分析化学会

     詳細を見る

    記述言語:日本語  

  • 液体クロマトグラフィー/キャピラリー電気泳動二次元糖鎖解析法の開発

    三木 太陽, 劉 晨晨, 木下 祥尚, 松森 信明, 山本 佐知雄, 木下 充弘, 川井 隆之

    日本分析化学会講演要旨集  2022年9月  (公社)日本分析化学会

     詳細を見る

    記述言語:日本語  

  • 核酸医薬品を対象とした超高感度キャピラリー電気泳動-質量分析の開発

    山下 愛斗, 藤村 泰地, 劉 晨晨, 木下 祥尚, 松森 信明, 川井 隆之

    日本分析化学会講演要旨集  2023年9月  (公社)日本分析化学会

     詳細を見る

    記述言語:日本語  

  • 一細胞薬物動態解析に向けた超高感度CE-MS分析法の開発

    藤村 泰地, 劉 晨晨, 鳥飼 浩平, 木下 祥尚, 松森 信明, 川井 隆之

    日本分析化学会講演要旨集  2023年9月  (公社)日本分析化学会

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    記述言語:日本語  

▼全件表示

MISC

  • 脂質ラフトを標的とする局所麻酔薬の作用機序 査読

    木下祥尚、松森信明

    月刊メディカル・サイエンス・ダイジェスト   2022年1月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(学術雑誌)  

  • 最先端医療の今 脂質ラフトを標的とする局所麻酔薬の作用機序

    木下 祥尚, 松森 信明

    Medical Science Digest   48 ( 1 )   50 - 51   2022年1月   ISSN:1347-4340

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    記述言語:日本語   出版者・発行元:(株)ニュー・サイエンス社  

    局所麻酔薬の作用機序についてはタンパク質仮説や脂質膜仮説など、いくつかの仮説が提唱されてきた。しかし、いずれの仮説も矛盾が指摘されており、新たなモデルの構築が熱望されている。筆者らは局所麻酔薬が細胞膜に存在する機能的膜領域「脂質ラフト」に作用することで、麻酔作用が発現するのではないかと考えた。このラフト標的仮説を検証するため、ラフトを模した相分離リポソームを作製し、麻酔薬がラフトに及ぼす影響を調査した。その結果、局所麻酔薬がラフトの形成を阻害することや、ラフト阻害能は麻酔の作用強度や細胞毒性と相関することを見出した。さらに、ラフト阻害能は脂質膜に対する局所麻酔薬の結合量ではなく、むしろ結合様式に依存することを明らかにした。本成果は効率的かつ安全な麻酔薬の調製に向けた指針を提唱する。(著者抄録)

  • 脂質ラフトを標的とする局所麻酔薬の作用機序

    木下祥尚, 松森信明

    月刊メディカル・サイエンス・ダイジェスト   48 ( 1 )   2022年   ISSN:1347-4340

     詳細を見る

  • 生体膜を標的にする天然有機化合物

    西村 慎一, 掛谷 秀昭, 松森信明

    化学と生物   2018年10月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(学術雑誌)  

    その他リンク: https://katosei.jsbba.or.jp/back_issue.php?bn_vol=56&bn_no=10

  • 脂質ラフトのNMR解析

    松森信明

    日本核磁気共鳴学会機関紙   2017年10月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(学術雑誌)  

    その他リンク: http://www.nmrj.jp/pdf/bulletin/bulletin_2017_8.pdf

産業財産権

特許権   出願件数: 4件   登録件数: 1件
実用新案権   出願件数: 0件   登録件数: 0件
意匠権   出願件数: 0件   登録件数: 0件
商標権   出願件数: 0件   登録件数: 0件

所属学協会

  • 日本化学会

  • American Chemical Society

  • 日本分析化学会

  • Biophysical Society

  • 日本核磁気共鳴学会

  • 日本ケミカルバイオロジー学会

  • 日本生物物理学会

  • 日本核磁気共鳴学会

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  • 日本化学会

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  • 日本分析化学会

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  • 日本ケミカルバイオロジー学会

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  • アメリカ化学会

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  • Biophysical Society

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委員歴

  • 日本ケミカルバイオロジー学会   世話人   国内

    2021年6月 - 2031年6月   

  • 日本分析化学会 九州支部   常任幹事   国内

    2020年4月 - 2024年3月   

  • 日本分析化学会   代議員  

    2018年4月 - 現在   

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    団体区分:学協会

    researchmap

  • 日本分析化学会   代議員   国内

    2018年4月 - 2025年3月   

  • 日本分析化学会 九州支部   幹事  

    2015年4月 - 現在   

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    団体区分:学協会

    researchmap

  • 日本分析化学会 九州支部   幹事   国内

    2015年4月 - 2020年3月   

  • 日本分析化学会 九州支部   常任幹事   国内

    2015年4月 - 2016年3月   

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学術貢献活動

  • 学術論文等の審査

    役割:査読

    2024年

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    種別:査読等 

    外国語雑誌 査読論文数:3

  • Biophysical Chemistry 国際学術貢献

    2023年1月 - 2024年6月

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    種別:学会・研究会等 

  • 学術論文等の審査

    役割:査読

    2023年

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    種別:査読等 

    外国語雑誌 査読論文数:5

    日本語雑誌 査読論文数:0

    国際会議録 査読論文数:0

    国内会議録 査読論文数:0

  • 学術論文等の審査

    役割:査読

    2022年

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    種別:査読等 

    外国語雑誌 査読論文数:4

    日本語雑誌 査読論文数:0

    国際会議録 査読論文数:0

    国内会議録 査読論文数:0

  • 実行委員

    第15回日本ケミカルバイオロジー学会  ( オンライン ) 2021年6月

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    種別:大会・シンポジウム等 

    参加者数:355

  • 学術論文等の審査

    役割:査読

    2021年

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    種別:査読等 

    外国語雑誌 査読論文数:2

    日本語雑誌 査読論文数:0

    国際会議録 査読論文数:0

    国内会議録 査読論文数:0

  • 実行委員会

    第15回ケミカルバイオロジー学会年会  ( 九州大学 ) 2020年6月

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    種別:大会・シンポジウム等 

    参加者数:500

  • 学術論文等の審査

    役割:査読

    2020年

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    種別:査読等 

    外国語雑誌 査読論文数:7

    日本語雑誌 査読論文数:0

    国際会議録 査読論文数:0

    国内会議録 査読論文数:0

  • 実行委員会

    第79回分析化学討論会  ( 北九州 ) 2019年5月

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    種別:大会・シンポジウム等 

    参加者数:500

  • 学術論文等の審査

    役割:査読

    2019年

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    種別:査読等 

    外国語雑誌 査読論文数:4

    日本語雑誌 査読論文数:1

    国際会議録 査読論文数:0

    国内会議録 査読論文数:0

  • 学術論文等の審査

    役割:査読

    2018年

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    種別:査読等 

    外国語雑誌 査読論文数:3

    日本語雑誌 査読論文数:0

    国際会議録 査読論文数:0

    国内会議録 査読論文数:0

  • 座長 国際学術貢献

    International Seminar on Biophysics and Chemical Biology of Biomembrane and Lipid Bilayers  ( 大阪大学 ) 2017年10月

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    種別:大会・シンポジウム等 

    参加者数:70

  • 学術論文等の審査

    役割:査読

    2017年

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    種別:査読等 

    外国語雑誌 査読論文数:4

    日本語雑誌 査読論文数:0

    国際会議録 査読論文数:0

    国内会議録 査読論文数:0

  • 座長(Chairmanship)

    日本分析化学会第65年会  ( 北海道大学工学部 ) 2016年9月

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    種別:大会・シンポジウム等 

  • 科研費審査

    役割:審査・評価

    日本学術振興会  2016年4月 - 2017年3月

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    種別:審査・学術的助言 

  • 実行委員

    日本分析化学会第64年会  ( 福岡市西区 九州大学伊都キャンパス ) 2015年9月

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    種別:大会・シンポジウム等 

    参加者数:500

  • 座長(Chairmanship)

    日本化学会年会  ( 名古屋 ) 2014年3月

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    種別:大会・シンポジウム等 

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共同研究・競争的資金等の研究課題

  • 潜在空間を構成・検証する生物活性の時空間定量計測手法開発・応用

    研究課題/領域番号:23H04881  2023年 - 2028年

    日本学術振興会・文部科学省  科学研究費助成事業  学術変革領域研究(A)

    菊地 和也, 蓑島 維文, 松森 信明, 野村 尚生

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    担当区分:研究分担者  資金種別:科研費

    本学術変革領域研究では、天然物(第1)と合成化合物ライブラリー(第2)に続く第3のリソース、化合物潜在空間を構築し、新しい生体機能解明や医薬・農薬シーズに結び付く生物活性分子デザイン法の新学理構築を目指す。この目標を達成するため、天然物及びその類縁体化合物の供与を受け、生きた状態での生物活性のイメージング解析、あるいは物理化学的手法による相互作用解析を行い、情報解析班へと提供する。

    CiNii Research

  • 麻酔作用機構の化学的解明

    2023年 - 2024年

    上原記念生命科学財団研究助成

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    担当区分:研究代表者  資金種別:受託研究

  • 膜タンパク質親和性天然物を起点とした天然物ー薬物複合体創薬への挑戦

    研究課題/領域番号:22K19115  2022年 - 2023年

    日本学術振興会  科学研究費助成事業  挑戦的研究(萌芽)

    松森 信明

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    担当区分:研究代表者  資金種別:科研費

    化合物ライブラリーを利用した創薬研究は、目的とする生理活性を有する化合物をいかに探索するかに主眼が置かれてきた。本提案では生理活性を指標とせず、標的膜タンパク質との強い親和性を有する天然物を探索する。ここで応募者の開発した膜タンパク質親和性天然物探索法を活用する。このようにして得られた天然物を起点として、その親和性を保ちつつ、抗体-薬物複合体のように低分子薬剤を結合させる。これにより、高い標的特異性と薬理活性を併せ持つ画期的な新薬を開発する創薬戦略を提案する。このように本研究は、申請者の開発した独自技術を起点とした「天然物-薬物複合体」医薬の創成と、それに基づく新たな創薬分野開拓を目指す。

    CiNii Research

  • 脂質ケミカルバイオロジー研究基盤の構築

    研究課題/領域番号:20H00405  2020年 - 2024年

    日本学術振興会  科学研究費助成事業  基盤研究(A)

    松森 信明, 老木 成稔, 岩本 真幸, 木下 祥尚, 神田 大輔

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    担当区分:研究代表者  資金種別:科研費

    本研究では、脂質-膜タンパク質間相互作用解析のプラットフォーム構築を目指す。このプラットフォームでは、「自己組織化単分子膜修飾SPR」や「膜タンパク質固定化金ナノ粒子」によって膜タンパク質特異的脂質を同定する。次いで「特異的脂質が膜タンパク質機能に与える影響」を精査する。さらに「特異的脂質が膜タンパク質会合状態に与える影響」「特異的脂質と膜タンパク質の共結晶化による複合体構造解析」までを行う。このようにして脂質-膜タンパク相互作用解析の新しい方法論を提示し、脂質機能および脂質多様性の解明に繋げる。さらに本研究を通して申請者の提唱する「脂質ケミカルバイオロジー」新学理の研究拠点形成を達成する。

    CiNii Research

  • 脂質2重膜の化学-物理変換機構が媒介するチャネル制御機構

    研究課題/領域番号:20H00497  2020年 - 2024年

    日本学術振興会  科学研究費助成事業  基盤研究(A)

    老木 成稔, 清水 貴浩, 岩本 真幸, 松森 信明, 許 岩

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    担当区分:研究分担者  資金種別:科研費

    生体膜は細胞にとって運動・エネルギー変換・情報伝達など様々な機能を担っており、その中心的な役割は膜蛋白質だけではなく脂質2重膜も担っている。細胞膜の複雑さを回避し、自由に化学的・物理的変化を起こし、それを正確に測定できる脂質2重膜での実験を行うことが本研究の目的である。脂質2重膜は外力だけでなく、その化学組成が変化することで張力や膜内電位が変化するのでこれを捉える方法を開発中である。これらの方法を確立することにより脂質2重膜の化学-物理変換機構を明らかにする。そしてこの変化に直接影響を受けるチャネルの機能を一分子測定することで脂質2重膜-チャネル相互作用の新しい機構を解明する。

    CiNii Research

  • 脂質が関与する化学コミュニケーション解明のための脂質認識天然物リガンドの探索

    研究課題/領域番号:20H04781  2020年 - 2021年

    日本学術振興会・文部科学省  科学研究費助成事業  新学術領域研究

      詳細を見る

    担当区分:研究代表者  資金種別:科研費

  • 脂質特異的タンパク質の網羅的解析法の開発

    2020年 - 2021年

    山田科学振興財団 研究援助

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    担当区分:研究代表者  資金種別:受託研究

  • 脂質が関与する化学コミュニケーション解明のための脂質認識天然物リガンドの探索

    研究課題/領域番号:20H04781  2020年

    日本学術振興会・文部科学省  科学研究費助成事業  新学術領域研究(研究領域提案型)

      詳細を見る

    担当区分:研究代表者  資金種別:科研費

  • 脂質ラフト阻害アッセイ法の開発と阻害剤の探索

    研究課題/領域番号:18K19149  2018年 - 2019年

    日本学術振興会  科学研究費助成事業  挑戦的研究(萌芽)

      詳細を見る

    担当区分:研究代表者  資金種別:科研費

  • 蛍光標識脂質を用いた脂質膜の動的秩序解析

    2016年3月 - 2018年3月

    日本 

      詳細を見る

    担当区分:研究代表者 

  • 蛍光標識脂質を用いた脂質膜の動的秩序解析

    研究課題/領域番号:16H00773  2016年 - 2017年

    日本学術振興会・文部科学省  科学研究費助成事業  新学術領域研究

      詳細を見る

    担当区分:研究代表者  資金種別:科研費

  • 脂質ケミカルバイオロジーの創出

    2015年4月 - 2018年3月

    九州大学 

      詳細を見る

    担当区分:研究代表者 

  • 脂質ケミカルバイオロジーの創成

    研究課題/領域番号:15H03121  2015年 - 2017年

    日本学術振興会  科学研究費助成事業  基盤研究(B)

      詳細を見る

    担当区分:研究代表者  資金種別:科研費

  • 海産梯子状ポリエーテル化合物イェッソトキシンの標的分子

    2014年4月 - 2016年3月

      詳細を見る

    担当区分:研究代表者 

  • 脂質ラフトにおける脂質分子の動的秩序解析

    2014年4月 - 2016年3月

      詳細を見る

    担当区分:研究代表者 

  • 脂質ラフトにおける脂質分子の動的秩序解析

    研究課題/領域番号:26102527  2014年 - 2015年

    日本学術振興会・文部科学省  科学研究費助成事業  新学術領域研究

      詳細を見る

    担当区分:研究代表者  資金種別:科研費

  • 海産梯子状ポリエーテル化合物イェッソトキシンの標的分子

    研究課題/領域番号:26102731  2014年 - 2015年

    日本学術振興会・文部科学省  科学研究費助成事業  新学術領域研究

      詳細を見る

    担当区分:研究代表者  資金種別:科研費

  • 生体膜構成脂質の機能を探る小分子の再発見と作用機構の解明

    2013年5月 - 2017年3月

      詳細を見る

    担当区分:研究分担者 

  • 生体膜構成脂質の機能を探る小分子の再発見と作用機構の解明

    研究課題/領域番号:25242073  2013年 - 2017年

    日本学術振興会  科学研究費助成事業  基盤研究(A)

      詳細を見る

    担当区分:研究分担者  資金種別:科研費

  • ERATO脂質構造活性プロジェクト

    2011年4月 - 2016年3月

    大阪大学 

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    担当区分:研究分担者 

    脂質分子の構造解析を通じて、機能分子である膜脂質や膜タンパク質の構造や動態を解明するための学術的基盤を作ることを目指しており、JST戦略目標「生命システムの動作原理の解明と活用のための基盤技術の創出」に資するものと期待されます。

▼全件表示

教育活動概要

  • 2019年前期 分析化学I、分析化学III、分析化学特論、アカデミック・フロンティア
    2018年前期 分析化学I、分析化学III、化学序説
    2017年後期 身の回りの化学
    2017年前期 分析化学I、分析化学III、分析化学特論II
    2016年後期 身の回りの化学
    2016年前期 分析化学I、分析化学III
    2015年後期 身の回りの化学
    2015年前期 分析化学I、分析化学特論II
    2014年後期 分析化学III、分析化学学生実験

担当授業科目

  • 化学序説Ⅱ

    2024年10月 - 2025年3月   後期

  • 化学序説Ⅰ

    2024年4月 - 2024年9月   前期

  • 分析化学Ⅲ

    2024年4月 - 2024年9月   前期

  • 化学序説Ⅱ

    2023年10月 - 2024年3月   後期

  • 化学序説Ⅰ

    2023年4月 - 2023年9月   前期

  • 化学特別講義Ⅳ

    2023年4月 - 2023年9月   前期

  • 分析化学Ⅲ

    2023年4月 - 2023年9月   前期

  • 分析化学特論ⅡA

    2023年4月 - 2023年6月   春学期

  • Advanced Analytical Chemistry ⅡA

    2023年4月 - 2023年6月   春学期

  • 化学序説Ⅱ

    2022年10月 - 2023年3月   後期

  • 化学序説Ⅰ

    2022年4月 - 2022年9月   前期

  • 分析化学Ⅲ

    2022年4月 - 2022年9月   前期

  • 分析化学Ⅰ

    2022年4月 - 2022年9月   前期

  • 化学序説(R3年度入学者及び2年次未進級者用)

    2021年4月 - 2022年3月   通年

  • 分析化学Ⅲ

    2021年4月 - 2021年9月   前期

  • 分析化学Ⅰ

    2021年4月 - 2021年9月   前期

  • 分析化学特論ⅡA

    2021年4月 - 2021年6月   春学期

  • 化学特別講義Ⅵ

    2020年4月 - 2021年3月   通年

  • 分析化学Ⅲ

    2020年4月 - 2020年9月   前期

  • 分析化学Ⅰ

    2020年4月 - 2020年9月   前期

  • 分析化学Ⅰ

    2019年4月 - 2019年9月   前期

  • 分析化学Ⅲ

    2019年4月 - 2019年9月   前期

  • 分析化学特論Ⅱ

    2019年4月 - 2019年9月   前期

  • 分析化学特論II

    2019年4月 - 2019年9月   前期

  • 分析化学III

    2019年4月 - 2019年9月   前期

  • 分析化学I

    2019年4月 - 2019年9月   前期

  • 分析化学Ⅲ

    2018年4月 - 2018年9月   前期

  • 化学序説

    2018年4月 - 2018年9月   前期

  • 分析化学Ⅰ

    2018年4月 - 2018年9月   前期

  • 身の回りの化学

    2017年12月 - 2018年2月   冬学期

  • 身の回りの化学

    2017年10月 - 2017年12月   秋学期

  • 分析化学Ⅲ

    2017年4月 - 2017年9月   前期

  • 分析化学特論Ⅱ

    2017年4月 - 2017年9月   前期

  • 分析化学Ⅰ

    2017年4月 - 2017年9月   前期

  • 身の回りの化学

    2016年12月 - 2017年2月   冬学期

  • 分析化学I

    2016年4月 - 2016年9月   前期

  • 分析化学III

    2016年4月 - 2016年9月   前期

  • 身の回りの化学

    2015年12月 - 2016年2月   冬学期

  • 分析化学III

    2015年10月 - 2016年3月   後期

  • 身の回りの化学

    2015年10月 - 2015年12月   秋学期

  • 分析化学I

    2015年4月 - 2015年9月   前期

  • 分析化学特論II

    2015年4月 - 2015年9月   前期

  • 分析化学III

    2014年10月 - 2015年3月   後期

  • 分析化学学生実験

    2014年10月 - 2015年3月   後期

▼全件表示

FD参加状況

  • 2023年10月   役割:司会   名称:ACS on Campus

    主催組織:学科

  • 2022年7月   役割:参加   名称:電子ジャーナルに関するFD

    主催組織:学科

  • 2022年3月   役割:参加   名称:メンタルヘルス講演会

    主催組織:全学

  • 2021年6月   役割:参加   名称:理系研究室の運営技術 ― ラボラトリーマネジメントという考え方 ―

    主催組織:学科

  • 2021年3月   役割:参加   名称:九州大学オンライン授業のグッドプラクティス 〜 オンデマンド型授業編〜

    主催組織:全学

  • 2020年12月   役割:参加   名称:新型コロナウィルス感染拡大状況での学生のメンタルヘルス

    主催組織:部局

  • 2020年11月   役割:参加   名称:事件等発生時の学生対応に関するFD・SD

    主催組織:全学

  • 2018年9月   役割:参加   名称:M2B システムFD

    主催組織:部局

  • 2018年3月   役割:司会   名称:学生に起こりやすい問題とその対応ー発達障害を中心にー

    主催組織:学科

  • 2016年2月   役割:参加   名称:化学部門FD

    主催組織:学科

▼全件表示

他大学・他機関等の客員・兼任・非常勤講師等

  • 2016年  京都大学薬学部  区分:非常勤講師  国内外の区分:国内 

    学期、曜日時限または期間:2016年6月

  • 2014年  大阪大学大学院理学研究科  区分:客員教員  国内外の区分:国内 

その他教育活動及び特記事項

  • 2024年  クラス担任  学部

  • 2023年  クラス担任  学部

  • 2022年  クラス担任  学部

  • 2021年  クラス担任  学部

  • 2020年  クラス担任  学部

  • 2019年  クラス担任  学部

  • 2018年  クラス担任  学部

  • 2017年  クラス担任  学部

  • 2017年  その他特記事項  フィンランドAbo Akademi大における博士審査主査

     詳細を見る

    フィンランドAbo Akademi大における博士審査主査

  • 2016年  クラス担任  学部

  • 2015年  クラス担任  学部

  • 2014年  クラス担任  学部

▼全件表示

社会貢献・国際連携活動概要

  • 研究内容のプレスリリースや公開講座による発信
    高校生や一般への模擬講義による化学の啓蒙活動

社会貢献活動

  • 低流量走査電子線散乱法による脂質膜の局所構造の解析−脂質ラフト様の膜ドメイン内部に複数の下部構造が存在することを発見−

    九州大学よりプレスリリース https://www.kyushu-u.ac.jp/f/41731/20_12_22_01.pdf  九州大学  2020年12月

     詳細を見る

    対象:社会人・一般, 学術団体, 企業, 市民団体, 行政機関

    種別:その他

  • 麻酔薬の「化学」

    福岡県立宗像高校 模擬講義  2020年12月

     詳細を見る

    対象:幼稚園以下, 小学生, 中学生, 高校生

    種別:セミナー・ワークショップ

  • 化学科後期特別談話会「麻酔の化学」

    九州大学理学部化学科  九州大学  2019年12月

     詳細を見る

    対象:社会人・一般, 学術団体, 企業, 市民団体, 行政機関

    種別:講演会

  • 麻酔の「化学」

    福岡県立筑前高校 模擬授業  2019年12月

     詳細を見る

    対象:幼稚園以下, 小学生, 中学生, 高校生

    種別:セミナー・ワークショップ

  • 麻酔の化学

    九州大学理学部 リカレント教育  2019年8月

     詳細を見る

    対象:幼稚園以下, 小学生, 中学生, 高校生

    種別:セミナー・ワークショップ

  • 局所麻酔薬が脂質ラフトを破壊 ~麻酔作用発現に関する新たなメカニズムの提案~

    九州大学よりプレスリリース https://www.kyushu-u.ac.jp/ja/researches/view/349  九州大学  2019年6月

     詳細を見る

    対象:社会人・一般, 学術団体, 企業, 市民団体, 行政機関

    種別:その他

    https://www.kyushu-u.ac.jp/ja/researches/view/349

  • 膜タンパク質の働きに深く関わる脂質を簡便に特定する方法の開発に成功 〜多様な脂質の生理機能の解明や医薬品開発に期待〜

    九州大学よりプレスリリースhttps://www.kyushu-u.ac.jp/ja/researches/view/320  九州大学  2019年2月

     詳細を見る

    対象:社会人・一般, 学術団体, 企業, 市民団体, 行政機関

    種別:その他

  • 肌の保湿バリア機能を示す成分であるセラミドの挙動をありのままに観察できる蛍光分子の開発に世界で初めて成功 - セラミドの機能解明につながる新たなツールとして期待 -

    九州大学よりプレスリリース https://www.kyushu-u.ac.jp/ja/researches/view/317  九州大学  2019年2月

     詳細を見る

    対象:社会人・一般, 学術団体, 企業, 市民団体, 行政機関

    種別:その他

  • 九州大学オープンキャンパス 理学部化学科紹介プログラム 「毒や薬から脂質膜までの分析化学」

    九州大学  九州大学伊都キャンパス  2017年8月

     詳細を見る

    対象:社会人・一般, 学術団体, 企業, 市民団体, 行政機関

    種別:講演会

  • 身の回りの化学物質:においや味から薬や毒まで

    山口県立徳山高校  2017年2月

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    対象:幼稚園以下, 小学生, 中学生, 高校生

    種別:セミナー・ワークショップ

  • 化学科後期特別談話会 「脂質膜の統合分析を目指して 脂質ケミカルバイオロジー」

    九州大学理学部化学科  九州大学  2016年12月

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    対象:社会人・一般, 学術団体, 企業, 市民団体, 行政機関

    種別:講演会

  • 化学科前期特別談話会  脂質膜の統合分析を目指して バイセルを用いたアプローチ

    九州大学理学部化学科  九州大学  2014年12月

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    対象:社会人・一般, 学術団体, 企業, 市民団体, 行政機関

    種別:講演会

  • 2014, 2015年度 大学入試センター試験問題作成委員

    2014年4月

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    対象:幼稚園以下, 小学生, 中学生, 高校生

    種別:その他

▼全件表示

メディア報道

  • 局所麻酔薬の作用発現に脂質膜破壊が関与か 新聞・雑誌

    科学新聞  2019年7月

     詳細を見る

    局所麻酔薬の作用発現に脂質膜破壊が関与か

  • 九大など、脂質の挙動をありのままに再現する蛍光プローブでラフトの形成機構を解明 新聞・雑誌

    日本経済新聞電子版  2017年3月

     詳細を見る

    九大など、脂質の挙動をありのままに再現する蛍光プローブでラフトの形成機構を解明

外国人研究者等の受け入れ状況

  • Abo Akademi University

    受入れ期間: 2018年3月  

    国籍:フィンランド共和国

  • National Tsing Hua University

    受入れ期間: 2017年9月   (期間):2週間未満

    国籍:台湾

  • Abo Akademi University

    受入れ期間: 2017年3月  

    国籍:フィンランド共和国

  • Åbo Akademi University

    受入れ期間: 2016年10月   (期間):2週間未満

    国籍:フィンランド共和国

  • Åbo Akademi University

    受入れ期間: 2015年10月   (期間):2週間未満

    国籍:フィンランド共和国

    専業主体:その他

海外渡航歴

  • 2017年12月

    滞在国名1:フィンランド共和国   滞在機関名1:Abo Akademi University

  • 2016年11月

    滞在国名1:大韓民国   滞在機関名1:慶州

  • 2015年12月

    滞在国名1:アメリカ合衆国   滞在機関名1:Honolulu

  • 2013年7月

    滞在国名1:アメリカ合衆国   滞在機関名1:University of Michigan

学内運営に関わる各種委員・役職等

  • 2024年4月 - 2025年3月   学部 学部長補佐

  • 2024年4月 - 2025年3月   研究院 研究院長補佐

  • 2024年4月 - 2025年3月   学府 学府長補佐

  • 2023年4月 - 2025年3月   全学 教職課程専門委員

  • 2019年4月 - 2023年3月   研究院 社会貢献推進委員会委員

  • 2018年4月 - 2019年3月   学科 学科長

  • 2018年4月 - 2019年3月   専攻 専攻長

  • 2018年4月 - 2019年3月   部門 部門長

  • 2016年4月 - 2017年3月   部門 教務主任

  • 2015年4月 - 2016年3月   部門 教務委員

▼全件表示