Download MendeleyThe Cytochrome P450 Catalyzing C-S Bond Formation in S-Heterocyclization of Chuangxinmycin Biosynthesis.
Shi, Y., Jiang, Z., Hu, X., Hu, X., Gu, R., Jiang, B., Zuo, L., Li, X., Sun, H., Zhang, C., Wang, L., Wu, L., Hong, B.(2021) Angew Chem Int Ed Engl 60: 15399-15404
- PubMed: 33884733
- DOI: https://doi.org/10.1002/anie.202015814
- Primary Citation of Related Structures:
6KFW - PubMed Abstract:
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.
Organizational Affiliation:
NHC Key Laboratory of Biotechnology of Antibiotics, CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Tiantan Xili, Beijing, 100050, China.
