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Enzyme-Controlled Nitrogen-Atom Transfer Enables Regiodivergent C−H Amination

Hyster, Todd K. and Farwell, Christopher C. and Buller, Andrew R. and McIntosh, John A. and Arnold, Frances H. (2014) Enzyme-Controlled Nitrogen-Atom Transfer Enables Regiodivergent C−H Amination. Journal of the American Chemical Society, 136 (44). pp. 15505-15508. ISSN 0002-7863. PMCID PMC4227740. http://resolver.caltech.edu/CaltechAUTHORS:20141027-111433880

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Abstract

We recently demonstrated that variants of cytochrome P450_(BM3) (CYP102A1) catalyze the insertion of nitrogen species into benzylic C–H bonds to form new C–N bonds. An outstanding challenge in the field of C–H amination is catalyst-controlled regioselectivity. Here, we report two engineered variants of P450_(BM3) that provide divergent regioselectivity for C–H amination—one favoring amination of benzylic C–H bonds and the other favoring homo-benzylic C–H bonds. The two variants provide nearly identical kinetic isotope effect values (2.8–3.0), suggesting that C–H abstraction is rate-limiting. The 2.66-Å crystal structure of the most active enzyme suggests that the engineered active site can preorganize the substrate for reactivity. We hypothesize that the enzyme controls regioselectivity through localization of a single C–H bond close to the iron nitrenoid.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://pubs.acs.org/doi/10.1021/ja509308vPublisherArticle
http://dx.doi.org/10.1021/ja509308vDOIArticle
http://pubs.acs.org/doi/suppl/10.1021/ja509308vPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227740/PubMed CentralArticle
ORCID:
AuthorORCID
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2014 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received: September 14, 2014; Published: October 17, 2014. We thank Dr. S. Virgil and the 3CS Catalysis Center at Caltech for assistance with HPLC and LC-MS analyses, and Pavle Nikolovski and the Molecular Observatory for assistance with X-ray crystallography and the Gordon and Betty Moore Foundation, the Beckman Institute, and the Sanofi-Aventis Bioengineering Research Program at Caltech for their generous support of the Molecular Observatory at Caltech. Operations at SSRL are supported by the US DOE and NIH. This work was supported by the Department of the Navy, Office of Naval Research (grant N00014-11-1-0205), and by the Jacobs Institute for Molecular Engineering for Medicine at Caltech. T.K.H. and J.A.M. are supported by Ruth L. Kirschstein National Research Service Awards (F32GM108143 and F32GM101792). C.C.F. is supported by an NSF Graduate Research Fellowship.
Funders:
Funding AgencyGrant Number
Department of Energy (DOE)UNSPECIFIED
NIHUNSPECIFIED
Office of Naval Research (ONR)N00014-11-1-0205
Jacobs Institute for Molecular Engineering for MedicineUNSPECIFIED
NIH Predoctoral FellowshipF32GM108143
NIH Predoctoral FellowshipF32GM101792
NSF Graduate Research FellowshipUNSPECIFIED
PubMed Central ID:PMC4227740
Record Number:CaltechAUTHORS:20141027-111433880
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20141027-111433880
Official Citation:Enzyme-Controlled Nitrogen-Atom Transfer Enables Regiodivergent C–H Amination Todd K. Hyster, Christopher C. Farwell, Andrew R. Buller, John A. McIntosh, and Frances H. Arnold Journal of the American Chemical Society 2014 136 (44), 15505-15508
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:50848
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:27 Oct 2014 20:48
Last Modified:20 Jul 2017 21:28

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