title: Tandem prenyltransferases catalyze isoprenoid elongation and complexity generation in biosynthesis of quinolone alkaloids.
abstract: 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.
authors: Yi
authors: Y
authors: Zou
authors: §College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P. R. China.
authors: Zhajun
authors: Z
authors: Zhan
authors: ∥Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China.
authors: Dehai
authors: D
authors: Li
authors: Mancheng
authors: M
authors: Tang
authors: Ralph A
authors: RA
authors: Cacho
authors: ⊥Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors: Kenji
authors: K
authors: Watanabe
authors: Yi
authors: Y
authors: Tang
mesh_terms: D000470:Alkaloids / Q000096:biosynthesis* / Q000737:chemistry; D055162:Biocatalysis; D004122:Dimethylallyltranstransferase / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D010407:Penicillium / Q000201:enzymology; D015363:Quinolones / Q000737:chemistry / Q000378:metabolism*; D013729:Terpenes / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D015363:Quinolones; D013729:Terpenes; D004122:Dimethylallyltranstransferase