Diverse Mechanisms for the Aromatic Hydroxylation: Insights into the Mechanisms of the Coumarin Hydroxylation by CYP2A6

IF 11.3 1区化学 Q1 CHEMISTRY, PHYSICAL ACS Catalysis Pub Date : 2024-10-20 DOI:10.1021/acscatal.4c05330

Zhenjia Gan, Jianqiang Feng, Jiabin Yin, Juping Huang, Binju Wang, John Z.H. Zhang

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Abstract

Different P450 isoforms may catalyze different types of reactions on the same substrate due to differences in their protein environments. To uncover how the spatial environment within the enzyme regulates substrate reactivity, we conducted quantum mechanics/molecular mechanics (QM/MM) simulations on the CYP2A6-catalyzed 7-hydroxylation of coumarin. The results revealed that water molecules can flexibly enter the active site of CYP2A6. In the absence of water molecules, the NIH shift mechanism was found to be the most favorable reaction pathway, leading to the keto intermediate that further undergoes the isomerization to form the C7-hydroxylated product. However, when water molecules are present at the active site, the N-protonation route can be facilitated by the active site waters and thus becomes the preferred one. Both the NIH mechanism and the N-protonation can rationalize the 1,2-H shift for the aromatic hydroxylation reactions. This study highlights that P450s can employ diverse and flexible mechanisms for aromatic hydroxylation, offering deeper insight into the mechanisms of P450-catalyzed aromatic hydroxylation reactions.

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芳香烃羟基化的多种机制：深入了解 CYP2A6 对香豆素的羟化机制

由于蛋白质环境的不同，不同的 P450 同工酶可能对相同底物催化不同类型的反应。为了揭示酶内空间环境如何调节底物反应性，我们对 CYP2A6 催化的香豆素 7- 羟基化反应进行了量子力学/分子力学（QM/MM）模拟。结果发现，水分子可以灵活地进入 CYP2A6 的活性位点。在没有水分子的情况下，NIH 转移机制被认为是最有利的反应途径，它导致酮中间体进一步发生异构化，形成 C7- 羟基化产物。然而，当活性位点存在水分子时，N-质子化途径会受到活性位点水的促进，从而成为首选途径。NIH 机制和 N-质子化机制都能使芳香烃羟化反应的 1,2-H 转变合理化。这项研究强调了 P450s 在芳香烃羟基化反应中可以采用多样而灵活的机制，为深入了解 P450 催化芳香烃羟基化反应的机制提供了新的视角。

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来源期刊

ACS Catalysis CHEMISTRY, PHYSICAL-

CiteScore

20.80

自引率

6.20%

发文量

1253

审稿时长

1.5 months

期刊介绍： ACS Catalysis is an esteemed journal that publishes original research in the fields of heterogeneous catalysis, molecular catalysis, and biocatalysis. It offers broad coverage across diverse areas such as life sciences, organometallics and synthesis, photochemistry and electrochemistry, drug discovery and synthesis, materials science, environmental protection, polymer discovery and synthesis, and energy and fuels. The scope of the journal is to showcase innovative work in various aspects of catalysis. This includes new reactions and novel synthetic approaches utilizing known catalysts, the discovery or modification of new catalysts, elucidation of catalytic mechanisms through cutting-edge investigations, practical enhancements of existing processes, as well as conceptual advances in the field. Contributions to ACS Catalysis can encompass both experimental and theoretical research focused on catalytic molecules, macromolecules, and materials that exhibit catalytic turnover.