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The Cytochrome P450 Catalyzing C−S Bond Formation in S ‐Heterocyclization of Chuangxinmycin Biosynthesis
Author(s) -
Shi Yuanyuan,
Jiang Zhibo,
Hu Xiaowen,
Hu Xiaomin,
Gu Renjie,
Jiang Bingya,
Zuo Lijie,
Li Xingxing,
Sun Hongmin,
Zhang Cong,
Wang Lifei,
Wu Linzhuan,
Hong Bin
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202015814
Subject(s) - biosynthesis , stereochemistry , chemistry , cytochrome p450 , monooxygenase , indole test , substrate (aquarium) , mutagenesis , hydrogen bond , enzyme , biochemistry , molecule , biology , organic chemistry , gene , mutation , ecology
Microbial sulfur‐containing secondary metabolites show various biological activities, but the C−S bond‐forming in their biosynthetic metabolism has not been thoroughly understood. Here, we present genetic, biochemical and structural characterization of a cytochrome P450 monooxygenase CxnD exhibiting C−S bond forming activity in S‐heterocyclization of chuangxinmycin biosynthesis. In vivo and in vitro analyses demonstrated that CxnD generated an indole‐fused dihydrothiopyran skeleton from a L ‐Trp‐derived thiol intermediate. Furthermore, X‐ray crystal structure of CxnD in complex with a substrate analogue and structure‐based mutagenesis revealed intimate details of the substrate binding mode. A radical mechanism initiated by abstraction of the imino hydrogen atom or an electron from indole group of the substrate was proposed for CxnD, which provided valuable insights into the molecular basis for the intra‐molecular C(sp 2 )−H thiolation by the P450 in chuangxinmycin biosynthesis.