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J Am Chem Soc. 2015 Apr 22;137(15):4980-3. doi: 10.1021/jacs.5b03022. Epub 2015 Apr 14.

Tandem prenyltransferases catalyze isoprenoid elongation and complexity generation in biosynthesis of quinolone alkaloids.

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§College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P. R. China.
∥Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China.
⊥Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.


Modification of natural products with prenyl groups and the ensuing oxidative transformations are important for introducing structural complexity and biological activities. Penigequinolones (1) are potent insecticidal alkaloids that contain a highly modified 10-carbon prenyl group. Here we reveal an iterative prenylation mechanism for installing the 10-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 dimethylallyl quinolone 6. The five-carbon side chain is then dehydrogenated by a flavin-dependent monooxygenase to give aryl diene 9, which serves as the electron-rich substrate for a second alkylation with dimethylallyl diphosphate to yield stryrenyl product 10. The completed, oxidized 10-carbon prenyl group then undergoes further structural morphing to yield yaequinolone C (12), the immediate precursor of 1. Our studies have therefore uncovered an unprecedented prenyl chain extension mechanism in natural product biosynthesis.

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