Flavin-linked oxidase catalyzes pyrrolizine formation of dichloropyrrole-containing polyketide extender unit in chlorizidine a

TitleFlavin-linked oxidase catalyzes pyrrolizine formation of dichloropyrrole-containing polyketide extender unit in chlorizidine a
Publication TypeJournal Article
Year of Publication2013
AuthorsMantovani S.M, Moore BS
JournalJournal of the American Chemical Society
Volume135
Pagination18032-18035
Date Published2013/12
Type of ArticleArticle
ISBN Number0002-7863
Accession NumberWOS:000328100000007
Keywordsbiosynthesis; cannabis-sativa; elucidation; enzyme; fatty-acids; heterologous expression; pathway; psychoactivity; streptomyces sp; synthase
Abstract

The marine alkaloid chlorizidine A contains chlorinated pyrroloisoindolone and pyrrolizine rings that are rare chemical features in bacterial natural products. Herein, we report the biosynthetic logic of their construction in Streptomyces sp. CNH-287 based on the identification of the chlorizidine A biosynthetic gene cluster. Using whole pathway heterologous expression and genetic manipulations, we show that chlorizidine A is assembled by a polyketide synthase that uniquely incorporates a fatty acid synthase-derived dichloropyrrolyl extender unit into the pyrroloisoindolone enzymatic product. We further provide the first biochemical characterization of a flavoenzyme associated with the oxidative formation of chlorizidine A's distinctive pyrrolizine ring. This work illuminates new enzymatic assembly line processes leading to rare nitrogen-containing rings in nature.

DOI10.1021/ja409520v
Short TitleJ. Am. Chem. Soc.
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