Flavin-linked oxidase catalyzes pyrrolizine formation of dichloropyrrole-containing polyketide extender unit in chlorizidine A.
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.
Center of Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California , San Diego, California 92093, United States.
Simone M
SM
Mantovani
Bradley S
BS
Moore
D053898:Biosynthetic Pathways; D005415:Flavins / Q000235:genetics / Q000378:metabolism*; D026121:Indole Alkaloids / Q000737:chemistry / Q000378:metabolism*; D005810:Multigene Family; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism*; D013302:Streptomyces / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
D005415:Flavins; D026121:Indole Alkaloids; D011758:Pyrroles; C581611:chlorizidine; D048630:Polyketide Synthases; D010088:Oxidoreductases