Total enzyme syntheses of napyradiomycins A1 and B1

TitleTotal enzyme syntheses of napyradiomycins A1 and B1
Publication TypeJournal Article
Year of Publication2018
AuthorsMcKinnie S.MK, Miles Z.D, Jordan P.A, Awakawa T., Pepper H.P, Murray L.AM, George J.H, Moore BS
JournalJournal of the American Chemical Society
Volume140
Pagination17840-17845
Date Published2018/12
Type of ArticleArticle
ISBN Number0002-7863
Accession NumberWOS:000454751800006
Keywordsbiosynthesis; chemistry; cyclization; halogenation; haloperoxidase; marine
Abstract

The biosynthetic route to the napyradiomycin family of bacterial meroterpenoids has been fully described 32 years following their original isolation and 11 years after their gene cluster discovery. The antimicrobial and cytotoxic natural products napyradiomycins A1 and B1 are produced using three organic substrates (1,3,6,8-tetrahydroxynaphthalene, dimethylallyl pyrophosphate, and geranyl pyrophosphate), and catalysis via five enzymes: two aromatic prenyltransferases (NapT8 and T9); and three vanadium dependent haloperoxidase (VHPO) homologues (NapH1, H3, and H4). Building upon the previous characterization of NapH1, H3, and T8, we herein describe the initial (NapT9, H1) and final (NapH4) steps required for napyradiomycin construction. This remarkably streamlined biosynthesis highlights the utility of VHPO enzymology in complex natural product generation, as NapH4 efficiently performs a unique chloronium-induced terpenoid cyclization to establish two stereocenters and a new carbon-carbon bond, and dual-acting NapH1 catalyzes chlorination and etherification reactions at two distinct stages of the pathway. Moreover, we employed recombinant napyradiomycin biosynthetic enzymes to chemoenzymatically synthesize milligram quantities in one pot in 1 day. This method represents a viable enantioselective approach to produce complex halogenated metabolites, like napyradiomycin B1, that have yet to be chemically synthesized.

DOI10.1021/jacs.8b10134
Short TitleJ. Am. Chem. Soc.
Student Publication: 
No
Research Topics: 
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