||Keitaro Suyama, Mika Mawatari, Daiki Tatsubo, Iori Maeda, Takeru Nose., Simple Regulation of the Self-Assembling Ability by Multimerization of Elastin-Derived Peptide (FPGVG)n Using Nitrilotriacetic Acid as a Building Block., ACS Omega, 10.1021/acsomega.0c06140. , 6, 8, 5705-5716, 2021.02.
||Xiaohui Liu, Keitaro Suyama, Takeru Nose, Miki Shimohigashi, Yasuyuki Shimohigashi, Bisphenol-C is the strongest bifunctional ERα-agonist and ERβ-antagonist due to magnified halogen bonding, PLoS ONE, https://doi.org/ 10.1371/journal.pone.0246583, 16, 2, e0246583, 2021.02.
||Keitaro Suyama, Shuhei Kaneko, Hitoshi Kesamaru, Xiaohui Liu, Ayami Matsushima, Yoshimitsu Kakuta, Takashi Okubo, Kazumi Kasatani, Takeru Nose, Evaluation of the Influence of Halogenation on the Binding of Bisphenol A to the Estrogen-Related Receptor γ, Chemical Research in Toxicology, 10.1021/acs.chemrestox.9b00379, 33, 4, 889-902, 2020.04, Halogenation of organic compounds is one the most important transformations in chemical synthesis and is used for the production of various industrial products. A variety of halogenated bisphenol analogs have recently been developed and are used as alternatives to bisphenol A (BPA), which is a raw material of polycarbonate that has adverse effects in animals. However, limited information is available on the potential toxicity of the halogenated BPA analogs. In the present study, to assess the latent toxicity of halogenated BPA analogs, we evaluated the binding and transcriptional activities of halogenated BPA analogs to the estrogen-related receptor γ(ERRÎ³), a nuclear receptor that contributes to the growth of nerves and sexual glands. Fluorinated BPA analogs demonstrated strong ERRγbinding potency, and inverse antagonistic activity, similar to BPA. X-ray crystallography and fragment molecular orbital (FMO) calculation revealed that a fluorine-substituted BPA analog could interact with several amino acid residues of ERRÎ³-LBD, strengthening the binding affinity of the analogs. The ERRγbinding affinity and transcriptional activity of the halogenated BPAs decreased with the increase in the size and number of halogen atom(s). The IC50 values, determined by the competitive binding assay, correlated well with the binding energy obtained from the docking calculation, suggesting that the docking calculation could correctly estimate the ERRγbinding potency of the BPA analogs. These results confirmed that ERRγhas a ligand binding pocket that fits very well to BPA. Furthermore, this study showed that the binding affinity of the BPA analogs can be predicted by the docking calculation, indicating the importance of the calculation method in the risk assessment of halogenated compounds..
||Xiaohui Liu, Keitaro Suyama, Junichi Shiki, Kohei Torikai, Takeru Nose, Miki Shimohigashi, Yasuyuki Shimohigashi, Bisphenol AF
Halogen bonding effect is a major driving force for the dual ERα-agonist and ERβ-antagonist activities, Bioorganic and Medicinal Chemistry, 10.1016/j.bmc.2019.115274, 28, 3, 2020.02, 17β-Estradiol (E2) is a natural steroid ligand for the structurally and physiologically independent estrogen receptors (ERs) ERα and ERβ. We recently observed that CF3-containing bisphenol AF (BPAF) works as an agonist for ERα but as an antagonist for ERβ. Similar results were also observed for the CCl3-containing bisphenol designated as HPTE. Both BPAF and HPTE are comprised of a tri-halogenated methyl group in the central alkyl moiety of their bisphenol structures, which strongly suggests that halogens contribute directly to the agonist/antagonist dual biological functions. We conducted this study to investigate the structure-activity relationships by assessing together newly synthesized CF3- and CBr3-containing bisphenol E analogs (BPE-X). We first tested bisphenols for their receptor binding ability and then for their transcriptional activities. Halogen-containing bisphenols were found to be fully active for ERα, but almost completely inactive for ERβ. When we examined these bisphenols for their inhibitory activities for E2 in ERβ, we observed that they worked as distinct antagonists. The ascending order of agonist/antagonist dual biological functions was BPE-F < BPE-Cl (HPTE) ≤ BPAF < BPE-Br, demonstrating that the electrostatic halogen bonding effect is a major driving force of the bifunctional ERα agonist and ERβ antagonist activities of BPAF..
||Xiaohui Liu, Hiroki Sakai, Mitsuhiro Nishigori, Keitaro Suyama, Tasuku Nawaji, Shin Ikeda, Makoto Nishigouchi, Hiroyuki Okada, Ayami Matsushima, Takeru Nose, Miki Shimohigashi, Yasuyuki Shimohigashi
, Receptor-binding Affinities of Bisphenol A and Its Next-generation Analogs for Human Nuclear Receptors, Toxicology and Applied Pharmacology, https://doi.org/10.1016/j.taap.2019.114610, in press, 2019.06, An endocrine-disrupting chemical Bisphenol A (BPA) binds specifically to a nuclear receptor (NR) named ERRγ. Although the importance of receptor-binding evaluation for human NRs is often stressed, the binding characteristics of so-called next-generation (NextGen) bisphenol compounds are still poorly understood. The ultimate objective of this investigation was to evaluate BPA and its NextGen analogs for their abilities to bind to 21 human NRs, the greatest members of NRs for which tritium-labeled specific ligands were available. After establishing the detailed assay conditions for each NR, the receptor binding affinities of total 11 bisphenols were evaluated in competitive binding assays. The results clearly revealed that BPA and the NextGen bisphenols of BPAF, BPAP, BPB, BPC, BPE, and BPZ were highly potent against one or more of NRs such as CAR, ERα, ERβ, ERRγ, and GR, with IC50 values of 3.3–73 nM. These bisphenols were suggested strongly to be disruptive to these NRs. BPM and BPP also appeared to be disruptive, but less potently. BPF exhibited only weak effects and only against estrogen-related NRs. Surprisingly, most doubtful bisphenol BPS was supposed not to be disruptive. The NRs to which BPA and NextGen bisphenols did not bind were RARα, RARβ, RARγ, and VDR. PPARγ, RORα, RORβ, RORγ, RXRα, RXRβ, and RXRγ, exhibited very weak interaction with these bisphenols. The ten remaining NRs, namely, ERRγ, ERβ, ERα, CAR, GR, PXR, PR, AR, LXRβ, and LXRα, showed distinctly strong binding to some bisphenols in this order, being likely to have consequential endocrine-disruption effects..
||Keitaro Suyama, Daiki Tatsubo, Wataru Iwasaki, Masaya Miyazaki, Yuhei Kiyota, Ichiro Takahashi, Iori Maeda, Takeru Nose, Enhancement of self-aggregation properties of linear elastin-derived short peptides by simple cyclization
strong self-aggregation properties of cyclo[FPGVG]n, consisting only of natural amino acids, Biomacromolecules, 10.1021/acs.biomac.8b00353, 19, 8, 3201-3211, 2018.06, Elastin-like peptides (ELP) consist of distinctive repetitive sequences, such as (VPGVG)n, exhibit temperature-dependent reversible self-assembly (coacervation), and have been considered to be useful for the development of thermo-responsive materials. Further fundamental studies evaluating coacervative properties of novel nonlinear ELPs could present design concepts for new thermo-responsive materials. In this study, we prepared novel ELPs, cyclic (FPGVG)n (cyclo[FPGVG]n, n = 1-5), and analyzed its self-assembly properties and structural characteristics. Cyclo[FPGVG]n (n = 3-5) demonstrated stronger coacervation capacity than the corresponding linear peptides. The coacervate of cyclo[FPGVG]5 was able to retain water-soluble dye molecules at 40°C, which implied that cyclo[FPGVG]5 could be employed as a base material of DDS (Drug Delivery System) matrices and other biomaterials. The results of molecular dynamics simulations and circular dichroism measurements suggested that a certain chain length was required for cyclo[FPGVG]n to demonstrate alterations in molecular structure that were critical to the exhibition of coacervation..
||Keitaro Suyama, Daiki Tatsubo, Hitoshi Kesamaru, Iori Maeda, Takeru Nose, Coacervation Property and Structural Analysis of Cyclic Analogs of Elastin-derived Peptide (FPGVG)n, Peptide Science 2016, 101-102, 2017.03, The elastin-derived peptide analog, (FPGVG)5, demonstrates a temperature- dependent self-association (coacervation) property. In this study, we prepared cyclic (FPGVG)n (n=1-5) analogs and investigated their coacervation and structural properties to assess their potential for use as a biomaterial. We found that the cyclic (FPGVG)n (n=3-5) analogs exhibited high coacervation ability. The results from the molecular dynamics simulation suggest that turn structures were important for coacervation of elastin-derived cyclic peptide analogs..
||Keitaro Suyama, Hitoshi Kesamaru, Daiki Tatsubo, Takeru Nose, Coacervation Properties and Structural Analysis of Aminobenzoyl-labeled Fluorescent Elastin-derived Peptides, Peptide Science 2015, 293-294, 2016.03, The elastin-derived peptide analog, (FPGVG)5, demonstrates a temperature- dependent self-association (coacervation) property. In this study, we prepared fluorescent-labeled (FPGVG)5 analogs, and evaluated their coacervation and fluorescent properties in order to assess their potential for use as a base material for fluorescent thermometers. We found that the fluorescent-labeled (FPGVG)5 analogs exhibited high coacervation ability. Results from the molecular dynamics calculation suggest that the fluorescent group is exposed on the surface of the molecule..
||Daiki Tatsubo, Keitaro Suyama, Takeru Nose, Fluorescence Analysis Using a Molecular Probe 1,8-ANS for Elucidation of the Molecular Mechanisms Underlying Coacervation of a Tryptophan-containing Elastin derived Dimeric Peptide, Peptide Science 2015, 95-96, 2016.03, A tryptophan-containing elastin-derived dimeric peptide (C(WPGVG)3)2 shows potent self-assembly activity. To elucidate the underlying coacervation mechanisms, we measured the fluorescence of (C(WPGVG)3)2 by using 1,8-ANS as a fluorescent probe. The results revealed that the peptide forms microaggregates at temperature and concentration lower than those at which visible coacervation occurs. These findings suggest that microaggregate formation is unrelated to the maturation of the coacervate drop, which is temperature-dependent..
||Keitaro Suyama, Suguru Taniguchi, Daiki Tatsubo, Iori Maeda, Takeru Nose, Dimerization effects on coacervation property of an elastin-derived synthetic peptide (FPGVG)5, Journal of Peptide Science, 10.1002/psc.2876, in press, 2016.03, A series of elastin-derived peptide (Phe-Pro-Gly-Val-Gly)5 dimers possessing high coacervation potential were synthesized. The new dimeric peptides showed significantly high coacervation ability compared to known elastin-derived peptide analogs. The molecular dynamics calculation results reveal that the dimeric peptides contain characteristic sheet-turnsheet motif involving a type II β-turn-like structure and form globular conformation..
||Kanako Nishio, Hirokazu Nishimura, Keitaro Suyama, Takeru Nose, Yasuyuki Shimohigashi, Halogenated Phe-containing endomorphin-2 analogs with mixed agonist and antagonist activities, Peptide Science 2012, in press, 2013.03.
||Yumi Kramitsu, Hirokazu Nishimura, Ryo Nakamura, Keitaro Suyama, Kazuhiro Matsumoto, Takeru Nose, Yasuyuki Shimohigashi, High-precision binding assay procedure of tachykinin receptor NK-1 for highly potent substance P analogs, Peptide Science 2012, in press, 2013.03.
||Ryo Nakamura, Hirokazu Nishimura, Keitaro Suyama, Takeru Nose, Yasuyuki Shimohigashi, The Effect of Halogenation of Phe-Phenyl Group of Two Consecutive Phe Residues Present in Neuropeptide Substance P on Its Specific Receptor Interaction, Peptide Science 2011, 157-158, 2012.03.
||Keitaro Suyama, Kazuhiro Matsumoto, Tsutomu Katsuki, Asymmetric Lewis Acid Catalysis of Aluminum(salalen) Complexes: Friedel-Crafts Reaction of Indole, Heterocycles, 10.3987/COM-08-S(F)93, 77, 817-824, 2009.02.
||Keitaro Suyama, Yoshifumi Sakai, Kazuhiro Matsumoto, Tsutomu Katsuki, Highly Enantioselective Hydrophosphonylation of Aldehydes: Base-Enhanced Aluminum-salalen Catalysis, Angewante Chemie, International Edition, 10.1002/anie.200905158, 49, 797-799, 2010.01.
||Kanako Nishio, Hirokazu Nishimura, Keitaro Suyama, Yoshinori Abe, Takeru Nose, Ayami Matsushima, Yasuyuki Shimohigashi, Effects of the Halogenation of Phe-Phenyl Group of Two Consecutive Residues in Endomorphin-2 on the Interaction with the μ-Opioid Receptors, Peptide Science 2011, 171-172, 2012.03.