Tandem Prenyltransferases Catalyze Isoprenoid Elongation and Complexity Generation in Biosynthesis of Quinolone Alkaloids

摘要

Modification of natural products with prenyl groups and the ensuing oxidative transformations are important for introducing structural complexity and biological activities. Understanding the different mechanisms Nature performs prenylation can lead to new enzymatic tools. Penigequinolones (>1) are potent insecticidal alkaloids that contain a highly modified ten-carbon prenyl group. Here we reveal an iterative prenylation mechanism for installing the ten-carbon unit using two aromatic prenyltransferases (PenI and PenG) present in the gene cluster of >1 from Penicillium thymicola. The initial Friedel-Crafts alkylation is catalyzed by PenI to yield the dimethylallyl quinolone >6. The five-carbon side chain is then dehydrogenated by a Flavin-dependent monooxygenase to an aryldiene >9, which serves as the electron-rich substrate for a second alkylation with dimethylallyl diphosphate to yield a stryrenyl product >10. The completed, oxidized ten-carbon prenyl group is then shown to undergo further structural morphing to yield yaequinolone C >12, the immediate precursor of >1. Our studies therefore uncover an unprecedented prenyl chain extension mechanism in natural product biosynthesis.