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Published December 5, 2018 | Supplemental Material
Journal Article Open

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

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.

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.

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Created:
August 19, 2023
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October 18, 2023