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Enzymatic Lactone-Carbene C‒H Insertion to Build Contiguous Chiral Centers

Zhou, Andrew Z. and Chen, Kai and Arnold, Frances H. (2020) Enzymatic Lactone-Carbene C‒H Insertion to Build Contiguous Chiral Centers. ACS Catalysis, 10 (10). pp. 5393-5398. ISSN 2155-5435. https://resolver.caltech.edu/CaltechAUTHORS:20200421-095315855

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Abstract

We report a biocatalytic platform of engineered cytochrome P411 enzymes (P450s with axial serine ligation) to carry out efficient lactone-carbene insertion into primary and secondary α-amino C–H bonds. Directed evolution of a P450 variant, P411-C10, yielded a lineage of enzyme variants capable of forming chiral lactone derivatives with high catalytic efficiency (up to 4000 TTN) and in a stereodivergent manner. For carbene insertion into secondary C–H bonds, a single mutation was discovered to invert the two contiguous chiral centers and lead to the opposite enantiomers of the same major diastereomers. This work demonstrates the utility of engineered enzymes for asymmetric catalysis and highlights the remarkable tunability of these genetically encoded biocatalysts for accessing the desired selectivities.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acscatal.0c01349DOIArticle
ORCID:
AuthorORCID
Chen, Kai0000-0002-3325-3536
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2020 American Chemical Society. Received: March 23, 2020; Revised: April 20, 2020; Published: April 21, 2020. This work was supported by NSF Division of Molecular and Cellular Biosciences grant MCB-1513007, US Army Research Office Institute for Collaborative Biotechnologies cooperative agreement W911NF-19-2-0026, and US Army Research Office Institute for Collaborative Biotechnologies contract W911NF-19-D-0001. K.C. thanks the Resnick Sustainability Institute at Caltech for fellowship support. Author Contributions: K.C. conceived the project. A.Z.Z. and K.C. performed all the experiments and analysis under the guidance of F.H.A. The manuscript was drafted by K.C. and edited by A.Z.Z. and F.H.A. The authors declare no competing financial interest.
Group:Resnick Sustainability Institute
Funders:
Funding AgencyGrant Number
NSFMCB-1513007
Army Research Office (ARO)W911NF-19-2-0026
Army Research Office (ARO)W911NF-19-D-0001
Resnick Sustainability InstituteUNSPECIFIED
Subject Keywords:cytochrome P450, directed evolution, carbene transfer, C−H functionalization, lactone
Issue or Number:10
Record Number:CaltechAUTHORS:20200421-095315855
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200421-095315855
Official Citation:Enzymatic Lactone-Carbene C–H Insertion to Build Contiguous Chiral Centers. Andrew Z. Zhou, Kai Chen, and Frances H. Arnold. ACS Catalysis 2020 10 (10), 5393-5398; DOI: 10.1021/acscatal.0c01349
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102695
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Apr 2020 17:09
Last Modified:15 May 2020 16:59

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