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

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    Origin and Control of Chemoselectivity in Cytochrome c Catalyzed Carbene Transfer into Si–H and N–H bonds
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2021, 143, 18, 7114–7123
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    https://doi.org/10.1021/jacs.1c02146
    Published April 28, 2021
    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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    Cite this: J. Am. Chem. Soc. 2021, 143, 18, 7114–7123
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.1c02146
    Published April 28, 2021
    Copyright © 2021 American Chemical Society
    Request reuse permissions

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