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Origin and Control of Chemoselectivity in Cytochrome c Catalyzed Carbene Transfer into Si–H and N–H bonds

Garcia-Borràs, Marc and Kan, S. B. Jennifer and Lewis, Russell D. and Tang, Allison and Jimenez-Osés, Gonzalo and Arnold, Frances H. and Houk, K. N. (2021) Origin and Control of Chemoselectivity in Cytochrome c Catalyzed Carbene Transfer into Si–H and N–H bonds. Journal of the American Chemical Society, 143 (18). pp. 7114-7123. ISSN 0002-7863. doi:10.1021/jacs.1c02146. https://resolver.caltech.edu/CaltechAUTHORS:20210429-132053494

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Abstract

A cytochrome c heme protein was recently engineered to catalyze the formation of carbon–silicon bonds via carbene insertion into Si–H bonds, a reaction that was not previously known to be catalyzed by a protein. High chemoselectivity toward C–Si bond formation over competing C–N bond formation was achieved, although this trait was not screened for during directed evolution. Using computational and experimental tools, we now establish that activity and chemoselectivity are modulated by conformational dynamics of a protein loop that covers the substrate access to the iron–carbene active species. Mutagenesis of residues computationally predicted to control the loop conformation altered the protein’s chemoselectivity from preferred silylation to preferred amination of a substrate containing both N–H and Si–H functionalities. We demonstrate that information on protein structure and conformational dynamics, combined with knowledge of mechanism, leads to understanding of how non-natural and selective chemical transformations can be introduced into the biological world.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.1c02146DOIArticle
https://doi.org/10.26434/chemrxiv.14102363.v1DOIDiscussion Paper
ORCID:
AuthorORCID
Garcia-Borràs, Marc0000-0001-9458-1114
Kan, S. B. Jennifer0000-0001-6371-8042
Lewis, Russell D.0000-0002-5776-7347
Jimenez-Osés, Gonzalo0000-0003-0105-4337
Arnold, Frances H.0000-0002-4027-364X
Houk, K. N.0000-0002-8387-5261
Additional Information:© 2021 American Chemical Society. Received: February 24, 2021; Published: April 28, 2021. This work was supported by the National Institutes of Health, National Institute for General Medical Sciences Grant GM-124480 (to K.N.H.); the National Science Foundation Division of Molecular and Cellular Biosciences Grant MCB-2016137 and the Division of Chemical, Bioengineering, Environmental, and Transport Systems Grant CBET-1937902 (to F.H.A.); the Spanish Ministry of Science and Innovation MICINN (Grant PID2019-111300GA-I00 to M.G.-B and Grants CTQ2015-70524-R and RYC-2013-14706 to G.J.-O.). M.G.-B. thanks the Ramón Areces Foundation for a postdoctoral fellowship, the Spanish MINECO for a Juan de la Cierva—Incorporación fellowship (Grant IJCI-2017-33411), and the Generalitat de Catalunya AGAUR for a Beatriu de Pinós H2020 MSCA-Cofund 2018-BP-00204 project. R.D.L. is supported by NIH National Research Service Award Training Grant 5 T32 GM07616. Computational resources were provided by the University of California, Los Angeles Institute for Digital Research and Education and the Extreme Science and Engineering Discovery Environment, which is supported by National Science Foundation Grant OCI-1053575. We thank Dr. K. Chen and Prof. X. Huang for helpful discussions and comments. Author Contributions. M.G.-B., S.B.J.K., and R.D.L. contributed equally. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
NIHGM-124480
NSFMCB-2016137
NSFCBET-1937902
Ministerio de Ciencia e Innovación (MICINN)PID2019-111300GA-I00
Ministerio de Ciencia e Innovación (MICINN)CTQ2015-70524-R
Ministerio de Ciencia e Innovación (MICINN)RYC-2013-14706
Fundación Ramón ArecesUNSPECIFIED
Ministerio de Economía y Competitividad (MINECO)IJCI-2017-33411
Generalitat de Catalunya2018-BP-00204
NIH Predoctoral Fellowship5 T32 GM07616
NSFOCI-1053575
Subject Keywords:Carbene compounds, Group 14 compounds, Peptides and proteins, Genetics, Conformation
Issue or Number:18
DOI:10.1021/jacs.1c02146
Record Number:CaltechAUTHORS:20210429-132053494
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210429-132053494
Official Citation:Origin and Control of Chemoselectivity in Cytochrome c Catalyzed Carbene Transfer into Si–H and N–H bonds. Marc Garcia-Borràs, S. B. Jennifer Kan, Russell D. Lewis, Allison Tang, Gonzalo Jimenez-Osés, Frances H. Arnold, and K. N. Houk. Journal of the American Chemical Society 2021 143 (18), 7114-7123; DOI: 10.1021/jacs.1c02146
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108869
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:29 Apr 2021 22:27
Last Modified:24 Jun 2021 20:22

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