記述言語：英語   出版者・発行元：Journal of the American Chemical Society  

Albomycins are unusual sulfur-containing nucleosides from the species of Streptomyces that exhibit potent antibiotic activities against both Gram-negative and Gram-positive bacteria including clinical pathogens. Previous studies demonstrated that the twitch radical SAM enzyme AbmM catalyzes an oxidative sulfur-for-oxygen swapping reaction converting CDP to a 4'-hydroxy-4'-thiocytidine 5'-diphosphate intermediate in the initial step of albomycin biosynthesis. However, the fate of this intermediate in the biosynthetic pathway has remained elusive. Herein, the above intermediate after 5'-dephosphorylation is shown to undergo AbmG-catalyzed transformations via a cryptic double phosphorylation of its 4'-hydroxyl group followed by C-O bond cleavage to yield 5'-oxo-4'-thiocytidine. X-ray crystal structure analysis and site-directed mutagenesis of AbmG revealed Glu188 as the general base to perform C5' deprotonation. Subsequent mechanistic studies using deuterated substrates demonstrated that the deprotonation at C5' is pro-R specific and likely occurs concerted with elimination of pyrophosphate from C4'. This study not only highlights a unique nucleoside kinase with lyase activity to complete an overall dehydration reaction but also fills the gaps in the biosynthesis of the atypical thiofuranose core essential to the biological activities of albomycins.

DOI： 10.1021/jacs.5c12827

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PubMed

記述言語：英語   出版者・発行元：Journal of the American Chemical Society  

AbmM is a radical S-adenosyl l-methionine (SAM) enzyme that catalyzes a radical initiated sulfur-for-oxygen swapping reaction, transforming the furanose ring of cytidine diphosphate (CDP) to a 4′-hydroxy-4′-thiofuranose product. While the function of AbmM has been demonstrated, the underlying mechanism regarding the formation of the radical intermediates during the reaction pathway remains to be fully established. To gain additional insight into this vital step in the biosynthesis of albomycin δ<inf>2</inf>, 2′-deoxy-2′-methylidene CDP was synthesized as a mechanistic probe. Upon incubation with AbmM and dithionite, a C1′ radical intermediate is generated from this mechanistic probe in the form of an allylic radical that can be trapped via oxidation to a sulfinate or a sulfenate versus reduction. Moreover, incubation of 2′-deoxy-2′-spirocyclopropryl CDP with AbmM also leads to a C1′ radical intermediate that triggers opening of the cyclopropane ring. In this case, however, the resulting C7′ terminal radical is not directly quenched but instead adds to the C5═C6 double bond of the cytosine base to form a new C7′–C6 bond. Taken together, these studies establish the intermediacy of a C1′ radical species and thus suggest radical propagation from the C4′ radical to the C1′ radical through cleavage of the C1′–O bond prior to the sulfur insertion step during the AbmM-catalyzed reaction.

DOI： 10.1021/jacs.5c10855

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記述言語：英語   出版者・発行元：Journal of Industrial Microbiology and Biotechnology  

Cyanobacteria are prolific producers of structurally diverse and biologically potent natural products, a subset of which feature guanidino moieties. Introduction and modification of the guanidine group confer tuned basicity and enable extensive hydrogen bonding, cation–π, and electrostatic interactions, facilitating high-affinity binding to numerous biological targets. Although the enzymatic processes responsible for guanidine modifications in cyanobacterial pathways remain somewhat obscure, recent investigations have begun to clarify the biosynthetic machinery that mediates these distinctive transformations. In this review, we summarize these advances, with particular emphasis on the enzymatic steps responsible for guanidine installation and tailoring. These enzymatic transformations include N-prenylation, cyclization, and tricyclic guanidinium formation, representing rare or previously undescribed biosynthetic strategies in nature. This review provides new insights into the metabolic and enzymatic versatility of cyanobacteria and a foundation for future advances in enzyme engineering and therapeutic discovery. One-Sentence Summary: This review highlights recent advances in understanding how cyanobacteria enzymatically install and modify guanidino groups to produce bioactive natural products.

DOI： 10.1093/jimb/kuaf024

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記述言語：英語   出版者・発行元：Nature Catalysis  

Carbon–sulfur bond-forming reactions in natural product biosynthesis largely involve Lewis acid/base chemistry with relatively few examples catalysed by radical S-adenosyl-l-methionine (SAM) enzymes. The latter have been limited to radical-mediated sulfur insertion into carbon–hydrogen bonds with the sulfur atom originating from a sacrificial auxiliary iron–sulfur cluster. Here we show that the radical SAM enzyme AbmM encoded in the albomycin biosynthetic gene cluster catalyses a sulfur-for-oxygen swapping reaction, transforming the furanose ring of cytidine 5′-diphosphate to a thiofuranose moiety that is essential for the antibacterial activity of albomycin δ<inf>2</inf>. Thus, in addition to its canonical function of mediating the reductive cleavage of SAM, the radical SAM catalytic cluster of AbmM appears to play a role in providing the sulfur introduced during the AbmM-catalysed reaction. These discoveries not only establish the origin of the thiofuranose core in albomycin δ<inf>2</inf> but, more importantly, also emphasize the functional diversity of radical SAM catalysis. (Figure presented.)

DOI： 10.1038/s41929-025-01367-w

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記述言語：英語   出版者・発行元：Chemical Society Reviews  

Nitrogen-centered radicals have emerged as versatile intermediates in natural product biosynthesis, playing pivotal roles in complex bond-forming and rearrangement reactions—including fragmentations, cyclizations, and dimerizations. These transformations enable the efficient construction of structurally intricate alkaloids, amino acids, cofactors, and other scaffolds that are often inaccessible via classical polar mechanisms. This review provides an overview of the enzymatic systems discovered and characterized over the past decade that harness nitrogen-centered radicals to mediate diverse biological transformations. Emphasis is placed on the enzymatic strategies for generating and precisely controlling these reactive species, with detailed discussions of their underlying mechanisms. These insights underscore the expanding role of nitrogen radical chemistry in biology and highlight its potential in the development of new biocatalytic platforms for synthetically challenging transformations.

DOI： 10.1039/d5cs00342c

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PubMed

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語   出版者・発行元：(公財)鈴木謙三記念医科学応用研究財団  

記述言語：日本語   出版者・発行元：(一社)日本生薬学会