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ORIGINAL RESEARCH article

Front. Chem.
Sec. Theoretical and Computational Chemistry
Volume 12 - 2024 | doi: 10.3389/fchem.2024.1471741
This article is part of the Research Topic Experimental and Theoretical Studies for Inert C-H Activation View all articles

Enhancing the High-Spin Reactivity in C-H Bond Activation by Iron(IV)-Oxo Species: Insights from Paclitaxel Hydroxylation by CYP2C8

Provisionally accepted
Dongxiao Yue Dongxiao Yue Hajime Hirao Hajime Hirao *
  • The Chinese University of Hong Kong, Shenzhen, Shenzhen, China

The final, formatted version of the article will be published soon.

    Previous theoretical studies have revealed that high-spin states possess flatter potential energy surfaces than low-spin states in reactions involving iron(IV)-oxo species of cytochrome P450 enzymes (P450s), nonheme enzymes, or biomimetic complexes. Therefore, actively utilizing highspin states to enhance challenging chemical transformations, such as C-H bond activation, represents an intriguing research avenue. However, the inherent instability of high-spin states relative to lowspin states in pre-reaction complexes often hinders their accessibility around the transition state, especially in heme systems with strong ligand fields. Counterintuitively, our investigation of the metabolic hydroxylation of paclitaxel by human CYP2C8 using a hybrid quantum mechanics and molecular mechanics (QM/MM) approach showed that the high-spin sextet state exhibits unusually stability, when the reaction follows a secondary reaction pathway leading to 6β-hydroxypaclitaxel.We thoroughly analyzed the factors contributing to the enhanced stabilization of the high-spin state, and the knowledge obtained could be instrumental in designing competent biomimetic catalysts and biocatalysts for C-H bond activation.

    Keywords: cytochrome P450, High-spin reactivity, C-H bond activation, QM/MM, CYP2C8, Paclitaxel

    Received: 28 Jul 2024; Accepted: 26 Aug 2024.

    Copyright: © 2024 Yue and Hirao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Hajime Hirao, The Chinese University of Hong Kong, Shenzhen, Shenzhen, China

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