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

  • Marc Garcia-Borràs*
    Marc Garcia-Borràs
    Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
    Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona, Carrer Maria Aurèlia Capmany 69, 17003 Girona, Spain
    *[email protected]
  • S. B. Jennifer Kan
    S. B. Jennifer Kan
    Division of Chemistry and Chemical Engineering 210-41, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, United States
  • Russell D. Lewis
    Russell D. Lewis
    Division of Biology and Bioengineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, United States
  • Allison Tang
    Allison Tang
    Division of Chemistry and Chemical Engineering 210-41, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, United States
    More by Allison Tang
  • Gonzalo Jimenez-Osés
    Gonzalo Jimenez-Osés
    CIC bioGUNE, Bizkaia Technology Park, Building 800, 48170 Derio, Spain
  • Frances H. Arnold*
    Frances H. Arnold
    Division of Biology and Bioengineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, United States
    Division of Chemistry and Chemical Engineering 210-41, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, United States
    *[email protected]
  • , and 
  • K. N. Houk*
    K. N. Houk
    Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
    *[email protected]
    More by K. N. Houk
Cite this: J. Am. Chem. Soc. 2021, 143, 18, 7114–7123
Publication Date (Web):April 28, 2021
https://doi.org/10.1021/jacs.1c02146
Copyright © 2021 American Chemical Society

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    Abstract

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    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.

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