A Mechanistic Understanding of the Distinct Regio‐ and Chemoselectivity of Multifunctional P450s by Structural Comparison of IkaD and CftA Complexed with Common Substrates

Author:

Jiang Peng12,Jin Hongbo1,Zhang Guangtao1,Zhang Wenjun123,Liu Wei1,Zhu Yiguang123,Zhang Changsheng123ORCID,Zhang Liping123

Affiliation:

1. Key Laboratory of Tropical Marine Bioresources and Ecology Guangdong Key Laboratory of Marine Materia Medica South China Sea Institute of Oceanology Chinese Academy of Science Guangzhou 510301 China

2. University of Chinese Academy of Science 19 Yuquan Road Beijing 100049 China

3. Sanya Institute of Oceanology Eco-Environmental Engineering Yazhou Scientific Bay Sanya 572000 China

Abstract

AbstractRegio‐ and chemoselective C−H activation at multi‐positions of a single molecule is fascinating but chemically challenging. The homologous cytochrome P450 enzymes IkaD and CftA catalyze multiple C−H oxidations on the same polycyclic tetramate macrolactam (PoTeM) ikarugamycin, with distinct regio‐ and chemoselectivity. Herein we provide mechanistic understanding of their functional differences by solving crystal structures of IkaD and CftA in complex with ikarugamycin and unnatural substrates. Distinct conformations of the F/G region in IkaD and CftA are found to differentiate the orientation of PoTeM substrates, by causing different binding patterns with polar moieties to determine site selection, oxidation order, and chemoselectivity. Fine‐tuning the polar subpocket altered the regioselectivity of IkaD, indicating that substrate re‐orientation by mutating residues distal to the oxidation site could serve as an important method in future engineering of P450 enzymes.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

General Medicine

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