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Alternate heme ligation steers activity and selectivity in engineered cytochrome P450-catalyzed carbene transfer reactions

Chen, Kai and Zhang, Shuo-Qing and Brandenberg, Oliver F. and Hong, Xin and Arnold, Frances H. (2018) Alternate heme ligation steers activity and selectivity in engineered cytochrome P450-catalyzed carbene transfer reactions. Journal of the American Chemical Society, 140 (48). pp. 16402-16407. ISSN 0002-7863. http://resolver.caltech.edu/CaltechAUTHORS:20181030-105013022

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Abstract

We report a biocatalytic platform of engineered cytochrome P450 enzymes to carry out carbene-transfer reactions using a lactone-based carbene precursor. By simply altering the heme-ligating residue, we obtained two enzymes that catalyze olefin cyclopropanation (Ser) or S–H bond insertion (Cys). Both enzymes exhibit high catalytic efficiency and stereoselectivity, thus enabling facile access to structurally diverse spiro[2.4]lactones and α-thio-γ-lactones. Computational studies revealed the mechanism of carbene S–H insertion and explain how the axial ligand controls reactivity and selectivity. This work expands the catalytic repertoire of hemeproteins and offers insights into how these enzymes can be tuned for new chemistry.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.8b09613DOIArticle
https://pubs.acs.org/doi/suppl/10.1021/jacs.8b09613PublisherSupporting Information
ORCID:
AuthorORCID
Chen, Kai0000-0002-3325-3536
Zhang, Shuo-Qing0000-0002-7617-3042
Brandenberg, Oliver F.0000-0001-5662-1234
Hong, Xin0000-0003-4717-2814
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2018 American Chemical Society. Received: September 10, 2018; Published: October 29, 2018. Financial support by NSF Division of Molecular and Cellular Biosciences grant MCB-1513007, National Natural Science Foundation of China (21702182), Zhejiang University, the Chinese “Thousand Youth Talents Plan”, and the “Fundamental Research Funds for the Central Universities” is gratefully acknowledged. O.F.B. acknowledges support from the Swiss National Science Foundation (P300PA_171225). Calculations were performed on the high-performance computing system at the Department of Chemistry, Zhejiang University. We thank X. Huang, D. K. Romney, R. K. Zhang, S. B. J. Kan, and R. D. Lewis in the Arnold lab and M. Garcia-Borràs in the K. Houk lab, UCLA, for helpful discussion and comments. We also thank N. Torian and the Caltech Mass Spectrometry Laboratory, and L. M. Henling and the Caltech X-ray Crystallography Facility, for analytical support, and B. M. Stoltz for use of a polarimeter. Author Contributions: K.C. and S.-Q.Z. contributed equally. The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
NSFMCB-1513007
National Natural Science Foundation of China21702182
Zhejiang UniversityUNSPECIFIED
Thousand Talents Plan of ChinaUNSPECIFIED
Fundamental Research Funds for the Central UniversitiesUNSPECIFIED
Swiss National Science Foundation (SNSF)P300PA_171225
Record Number:CaltechAUTHORS:20181030-105013022
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20181030-105013022
Official Citation:Alternate Heme Ligation Steers Activity and Selectivity in Engineered Cytochrome P450-Catalyzed Carbene-Transfer Reactions. Kai Chen, Shuo-Qing Zhang, Oliver F. Brandenberg, Xin Hong, and Frances H. Arnold. Journal of the American Chemical Society 2018 140 (48), 16402-16407. DOI: 10.1021/jacs.8b09613
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90494
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:30 Oct 2018 20:23
Last Modified:10 Dec 2018 19:46

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