Insights into Arsenic Secondary Metabolism in Actinomycetes from the Structure and Biosynthesis of Bisenarsan

Abstract

The unique bioactivities of arsenic-containing secondary metabolites have been revealed recently, but studies on arsenic secondary metabolism in microorganisms have been extremely limited. Here, we focused on the organoarsenic metabolite with an unknown chemical structure, named bisenarsan, produced by well-studied model actinomycetes and elucidated its structure by combining feeding of the putative biosynthetic precursor (2-hydroxyethyl)­arsonic acid to Streptomyces lividans 1326 and detailed NMR analyses. Bisenarsan is the first characterized actinomycete-derived arsenic secondary metabolite and may function as a prototoxin form of an antibacterial agent or be a detoxification product of inorganic arsenic species. We also verified the previously proposed genes responsible for bisenarsan biosynthesis, especially the (2-hydroxyethyl)­arsonic acid moiety. Notably, we suggest that a C–As bond in bisenarsan is formed by the intramolecular rearrangement of a pentavalent arsenic species (arsenoenolpyruvate) by the cofactor-independent phosphoglycerate mutase homologue BsnN, that is entirely distinct from the conventional biological C–As bond formation through As-alkylation of trivalent arsenic species by S-adenosylmethionine-dependent enzymes. Our findings will speed up the development of arsenic natural product biosynthesis.

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“…Feeding studies and NMR analysis have revealed the chemical structure of the organoarsenic metabolite, bisenarsan 29 , from the actinomycete, Streptomyces lividans 1326. 28 Identification of the bisenarsan gene cluster revealed that the C–As bond is formed by the cofactor-independent phosphoglycerate mutase homologue, BsnN via an intramolecular rearrangement of arsenoenolpyruvate.…”