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Engineered P450 Atom-Transfer Radical Cyclases are Bifunctional Biocatalysts: Reaction Mechanism and Origin of Enantioselectivity

Cite this: J. Am. Chem. Soc. 2022, 144, 29, 13344–13355
Publication Date (Web):July 13, 2022
https://doi.org/10.1021/jacs.2c04937
Copyright © 2022 American Chemical Society

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    Abstract

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    New-to-nature radical biocatalysis has recently emerged as a powerful strategy to tame fleeting open-shell intermediates for stereoselective transformations. In 2021, we introduced a novel metalloredox biocatalysis strategy that leverages the innate redox properties of the heme cofactor of P450 enzymes, furnishing new-to-nature atom-transfer radical cyclases (ATRCases) with excellent activity and stereoselectivity. Herein, we report a combined computational and experimental study to shed light on the mechanism and origins of enantioselectivity for this system. Molecular dynamics and quantum mechanics/molecular mechanics (QM/MM) calculations revealed an unexpected role of the key beneficial mutation I263Q. The glutamine residue serves as an essential hydrogen bond donor that engages with the carbonyl moiety of the substrate to promote bromine atom abstraction and enhance the enantioselectivity of radical cyclization. Therefore, the evolved ATRCase is a bifunctional biocatalyst, wherein the heme cofactor enables atom-transfer radical biocatalysis, while the hydrogen bond donor residue further enhances the activity and enantioselectivity. Unlike many enzymatic stereocontrol rationales based on a rigid substrate binding model, our computations demonstrate a high degree of rotational flexibility of the allyl moiety in an enzyme–substrate complex and succeeding intermediates. Therefore, the enantioselectivity is controlled by the radical cyclization transition states rather than the substrate orientation in ground-state complexes in the preceding steps. During radical cyclization, anchoring effects of the Q263 residue and steric interactions with the heme cofactor concurrently control the π-facial selectivity, allowing for highly enantioselective C–C bond formation. Our computational findings are corroborated by experiments with ATRCase mutants generated from site-directed mutagenesis.

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    Cited By

    This article is cited by 5 publications.

    1. Xin Liu, Sheng Xu, Heyu Chen, Yang Yang. Unnatural Thiamine Radical Enzymes for Photobiocatalytic Asymmetric Alkylation of Benzaldehydes and α-Ketoacids. ACS Catalysis 2024, Article ASAP.
    2. Thomas W. Thorpe, James R. Marshall, Nicholas J. Turner. Multifunctional Biocatalysts for Organic Synthesis. Journal of the American Chemical Society 2024, 146 (12) , 7876-7884. https://doi.org/10.1021/jacs.3c09542
    3. Matteo Capone, Gianluca Dell’Orletta, Bryce T. Nicholls, Gregory D. Scholes, Todd K. Hyster, Massimiliano Aschi, Isabella Daidone. Evidence of a Distinctive Enantioselective Binding Mode for the Photoinduced Radical Cyclization of α-Chloroamides in Ene-Reductases. ACS Catalysis 2023, 13 (23) , 15310-15321. https://doi.org/10.1021/acscatal.3c03934
    4. Huan Guo, Ningning Sun, Juan Guo, Tai‐Ping Zhou, Langyu Tang, Wentao Zhang, Yaming Deng, Rong‐Zhen Liao, Yuzhou Wu, Guojiao Wu, Fangrui Zhong. Expanding the Promiscuity of a Copper‐Dependent Oxidase for Enantioselective Cross‐Coupling of Indoles. Angewandte Chemie 2023, 134 https://doi.org/10.1002/ange.202219034
    5. Huan Guo, Ningning Sun, Juan Guo, Tai‐Ping Zhou, Langyu Tang, Wentao Zhang, Yaming Deng, Rong‐Zhen Liao, Yuzhou Wu, Guojiao Wu, Fangrui Zhong. Expanding the Promiscuity of a Copper‐Dependent Oxidase for Enantioselective Cross‐Coupling of Indoles. Angewandte Chemie International Edition 2023, 134 https://doi.org/10.1002/anie.202219034