September 22, 2019  |  

Molecular basis for the final oxidative rearrangement steps in chartreusin biosynthesis.

Authors: Wang, Yi Shuang and Zhang, Bo and Zhu, Jiapeng and Yang, Cheng Long and Guo, Yu and Liu, Cheng Li and Liu, Fang and Huang, Huiqin and Zhao, Suwen and Liang, Yong and Jiao, Rui Hua and Tan, Ren Xiang and Ge, Hui Ming

Oxidative rearrangements play key roles in introducing structural complexity and biological activities of natural products biosynthesized by type II polyketide synthases (PKSs). Chartreusin (1) is a potent antitumor polyketide that contains a unique rearranged pentacyclic aromatic bilactone aglycone derived from a type II PKS. Herein, we report an unprecedented dioxygenase, ChaP, that catalyzes the final a-pyrone ring formation in 1 biosynthesis using flavin-activated oxygen as an oxidant. The X-ray crystal structures of ChaP and two homologues, docking studies, and site-directed mutagenesis provided insights into the molecular basis of the oxidative rearrangement that involves two successive C-C bond cleavage steps followed by lactonization. ChaP is the first example of a dioxygenase that requires a flavin-activated oxygen as a substrate despite lacking flavin binding sites, and represents a new class in the vicinal oxygen chelate enzyme superfamily.

Journal: Journal of the American chemical society
DOI: 10.1021/jacs.8b06623
Year: 2018

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