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

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.

SUBMITTER: Mantovani SM

PROVIDER: S-EPMC3887146 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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

Mantovani Simone M SM Moore Bradley S BS

Journal of the American Chemical Society 20131121 48

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 ...[more]

PMID: 24246014

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