解析P450催化芳环羟基化反应的机理: 氧化芳烃途径以及区域选择性的探究

doi:10.1016/S1872-2067(24)60234-2

催化学报 ›› 2025, Vol. 70: 420-430.DOI: 10.1016/S1872-2067(24)60234-2

解析P450催化芳环羟基化反应的机理: 氧化芳烃途径以及区域选择性的探究

黄群^a^,^b^,^e^,¹, 张璇^c^,^f^,¹, 孙光武^d^,¹, 邱瑞英^b^,¹, 罗兰^e, 王翠珍^b, 高龙威^a, 高兵^d, 陈波^b^,^*(), 王斌举^c^,^*(), 王健博^a^,^b^,^*()

^a浙江大学医学院, “多脏器衰竭预警与干预”教育部重点实验室, 浙江大学第二附属医院综合ICU及药物生物技术研究所, 浙江杭州 310058
^b湖南师范大学化学化工学院, 化学生物学与中药研究教育部重点实验室, 植化单体开发与利用湖南省重点实验室, 湖南长沙 410081
^c厦门大学化学化工学院, 固体表面物理化学国家重点实验室, 福建省理论与计算化学重点实验室, 福建厦门 361005
^d湖南大学化学化工学院, 化学生物学与纳米医学研究所, 化学/生物传感与化学计量学国家重点实验室, 湖南长沙 410082
^e重庆理工大学药学与生物工程学院, 重庆 400054
^f宁波大学新药技术研究院, 天体化学与空间生命-钱学森空间科学协同研究中心, 浙江宁波 315211

收稿日期:2024-11-12 接受日期:2024-12-21 出版日期:2025-03-18 发布日期:2025-03-20
通讯作者: * 电子信箱: dr-chenpo@vip.sina.com (陈波),wangbinju2018@xmu.edu.cn (王斌举),jwang2023@zju.edu.cn (王健博).
作者简介:¹共同第一作者.
基金资助:
国家重点研发计划(2023YFA0914100/2023YFA0914102);国家自然科学基金(22077029);国家自然科学基金(22477110);国家自然科学基金(22034002);国家自然科学基金(22276049);国家自然科学基金(22073077);国家自然科学基金(22001065);中央高校基本科研业务费(226202400061);中央高校基本科研业务费(226202300100);湖南省杰出青年科学基金(2021JJ10034);重庆市教委科学技术研究项目(KJQN202401148);植化单体开发与利用湖南省重点实验室开放基金(23010104)

Decoding the mechanism of P450-catalyzed aromatic hydroxylation: Uncovering the arene oxide pathway and insights into the regioselectivity

Qun Huang^a^,^b^,^e^,¹, Xuan Zhang^c^,^f^,¹, Guangwu Sun^d^,¹, Rui-ying Qiu^b^,¹, Lan Luo^e, Cuizhen Wang^b, Longwei Gao^a, Bing Gao^d, Bo Chen^b^,^*(), Binju Wang^c^,^*(), Jian-bo Wang^a^,^b^,^*()

^aKey Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, Department of General Intensive Care Unit of the Second Affiliated Hospital and Institute of Pharmaceutical Biotechnology, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
^bKey Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education) and Key Laboratory of Phytochemical R&D of Hunan Province, College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, Hunan, China
^cState Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen361005, Fujian, China
^dState Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Institute of Chemical Biology and Nanomedicine, Hunan University, Changsha 410082, Hunan, China
^eSchool of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
^fInstitute of Drug Discovery Technology and Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Ningbo University, Ningbo 315211, Zhejiang, China

Received:2024-11-12 Accepted:2024-12-21 Online:2025-03-18 Published:2025-03-20
Contact: * E-mail: dr-chenpo@vip.sina.com (B. Chen),wangbinju2018@xmu.edu.cn (B. Wang),jwang2023@zju.edu.cn (J. Wang).
About author:¹Contributed equally to this work.
Supported by:
National Key Research and Development Program of China(2023YFA0914100/2023YFA0914102);National Natural Science Foundation of China(22077029);National Natural Science Foundation of China(22477110);National Natural Science Foundation of China(22034002);National Natural Science Foundation of China(22276049);National Natural Science Foundation of China(22073077);National Natural Science Foundation of China(22001065);Fundamental Research Funds for the Central Universities(226202400061);Fundamental Research Funds for the Central Universities(226202300100);Science Fund for Distinguished Young Scholars of Hunan Province(2021JJ10034);Scientific and Technological Research Program of Chongqing Municipal Education Commission(KJQN202401148);Open Fund of Key Laboratory of Phytochemistry R&D of Hunan Province of Hunan Normal University(23010104)

摘要/Abstract

摘要：

P450酶催化的芳环羟基化在芳香族化合物的解毒、生物合成和潜在致癌作用中均起着重要作用. 虽然其催化机理与烷烃的羟基化一样, 是由高反应活性的血红素-Fe(IV)=O (Cpd I)介导, 但相比之下, Cpd I与芳香族π系统的反应更为复杂. 尽管P450催化芳环羟基化的机理被研究了几十年, 目前仍存在许多争议. 此外, 实验表明取代芳香族化合物的羟基化通常发生在邻位或对位, 该区域选择性是否与已知或未知中间体的生成有关, 还没有相关研究. 因此, 有关P450催化芳环羟基化的真实过程以及机理细节仍有待深入研究.

有机分子中, 氟元素的引入可以显著提高化合物的代谢稳定性, 据此我们推测含氟芳香族化合物, 可能是P450催化芳环羟基化反应中获得稳定中间体的合适底物. 因此, 本文以α-氟代苯乙酸乙酯为化学探针, P450-BM3为催化剂, 以期检测出相应的关键中间体, 详细阐明P450催化芳环羟基化的机理. 通过对α-氟代苯乙酸乙酯转化体系进行反应时间尺度监测, 成功捕获了芳烃1,2-氧化物和芳烃2,3-氧化物两个环氧化中间体, 并对其进行了制备与分离. 结合两个环氧化中间体的质谱、核磁及其Diels-Alder反应衍生物的晶体结构检测分析, 首次对两种环氧化中间体的结构进行了确定. 进一步利用分离所得的两个环氧化中间体进行反应性探究, 发现其均可通过NIH迁移, 形成不稳定的酮中间体. 该中间体迅速发生重排, 形成芳环羟化产物2-氟-2-(2-羟基苯基)乙酸乙酯. 而该芳环羟化产物可自发脱氟, 进一步在还原酶作用下生成脱氟产物2-(2-羟基苯基)乙酸乙酯, 这一系列证据证实了“芳烃氧化物形成-NIH迁移”机制确实存在于P450催化芳环的羟化反应中. 此外, 通过混合簇连续体(HCC)模型计算对P450催化芳环羟基化反应过程和区域选择性机理进行了解释, 结合NIH迁移的条件, 推测环氧化中间体的化学性质以及水分子的影响是影响其环氧结构开环的关键因素. 最后, 为了验证P450催化芳环羟基化的“环氧化物形成-NIH迁移”机制的普遍性, 本文进一步探究了P450催化天然底物肉桂酸甲酯的芳环羟基化过程. 通过对其进行反应时间尺度监测, 成功捕获了一个手性环氧中间体, 利用分离所得的环氧化中间体进行反应性测试, 发现其能自发转化成邻羟基产物3-(2-羟基苯基)-2-丙烯酸甲酯, 这进一步证明了芳烃氧化物途径确实参与了P450催化的芳环羟基化.

综上, 本文成功证明了P450催化芳环羟基化的“芳烃氧化物形成-NIH迁移”机制并对其区域选择性机理进行了解析, 不仅为P450催化芳环羟基化的芳烃氧化物途径提供了最直接的证据, 为该反应过程中存在的区域选择性提供了新的见解, 而且也为实现芳香化合物的不对称去芳构化提供了一种新的途径.

关键词: 芳环羟基化, 细胞色素P450, 芳烃氧化物, 区域选择性, 脱芳构化

Abstract:

P450 enzymes-catalyzed aromatic hydroxylation plays an important role in detoxification, biosynthesis, and potential carcinogenic effect of aromatic compounds. Though it has been explored for decades, the actual process of aromatic hydroxylation and mechanism of regioselectivity catalyzed by cytochrome P450 monooxygenases remained ambiguous. Here, we have resolved these issues. With a stable chiral organofluorine probe, and especially with X-ray data of two isolated arene oxides derivatives, we demonstrate that an arene oxide pathway is definitely involved in P450-catalyzed aromatic hydroxylation. By the capture, isolation, identification and reactivity exploration of the arene 1,2-oxide and arene 2,3-oxide intermediates, together with advanced QM calculations, the mechanism of how two intermediates go to the same product has been elucidated. In addition to the model substrate, we also confirmed that an arene oxide intermediate is involved in the P450-catalyzed hydroxylation pathway of a natural product derivative methyl cinnamate, which indicates that this intermediate appears to be universal in P450-catalyzed aromatic hydroxylation. Our work not only provides the most direct evidence for the arene oxide pathway and new insights into the regioselectivity involved in P450-catalyzed aromatic hydroxylation, but also supplies a new synthetic approach to achieve the dearomatization of aromatic compounds.

Key words: Aromatic hydroxylation, Cytochrome P450, Arene oxide, Regioselectivity, Dearomatization

黄群, 张璇, 孙光武, 邱瑞英, 罗兰, 王翠珍, 高龙威, 高兵, 陈波, 王斌举, 王健博. 解析P450催化芳环羟基化反应的机理: 氧化芳烃途径以及区域选择性的探究[J]. 催化学报, 2025, 70: 420-430.

Qun Huang, Xuan Zhang, Guangwu Sun, Rui-ying Qiu, Lan Luo, Cuizhen Wang, Longwei Gao, Bing Gao, Bo Chen, Binju Wang, Jian-bo Wang. Decoding the mechanism of P450-catalyzed aromatic hydroxylation: Uncovering the arene oxide pathway and insights into the regioselectivity[J]. Chinese Journal of Catalysis, 2025, 70: 420-430.

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图/表 6

Scheme 1. Aromatic hydroxylation catalyzed by cytochrome P450. (a) Mechanism speculations for aromatic hydroxylation catalyzed by cytochrome P450. (b) Regioselectivity of aromatic hydroxylation catalyzed by P450 enzyme: usually occurs at the ortho- or para-sites, while the meta-site is rare. (c) P450-BM3-catalyzed aromatic hydroxylation leading to remote induced defluorination in our previous work.

Fig. 1. Time-scale monitoring of the conversion of 1. The GC analysis of enzymatic conversion of 1 by whole cells harboring P450-BM3 (a) and purified enzyme (b). Details of the reaction systems have been put in the SI.

Fig. 2. Isolation and identification of arene oxides 3 and 5. The GC analysis of purity of 3 (a) and 5 (b) after silica gel column chromatographic separation. (c) The structures of the derivatives of 3 and 5 as determined by X-ray structure analysis.

Fig. 3. Investigation on the arene oxide pathway in aromatic hydroxylation catalyzed by P450. (a) Proposed arene oxide pathway of aromatic hydroxylation catalyzed by P450. The GC analysis of enzymatic conversion of 3 (b) and 5 (c) by purified NemA. The GC analysis of enzymatic conversion of 3 (d) and 5 (e) by purified NemA on time-scale.

Fig. 4. B3LYP/6-311++G(d,p) relative free energies (in kcal/mol) for the rearrangement processes. (a) 3-1 → 7; (b) 3-2 → 7; (c) 5-1 → 7; (d) 5-2 → 7 in aqueous solution (no enzyme) with explicit water molecules in the HCC calculations. R: -COOCH2CH3.

Fig. 5. Verification of the universality of the arene oxide pathway in P450-catalyzed aromatic hydroxylation by non-fluorinated substrate. (a) GC analysis of enzymatic conversion of 8 by purified P450-BM3 (A330Y/T438L). (b) The GC analysis of enzymatic conversion of 8 by purified P450-BM3 (A330Y/T438L) on time-scale. (c) The GC analysis of spontaneous conversion of 9 → 10 on time-scale. (d) The GC analysis of enzymatic conversion of 9 → 10 with purified P450-BM3 (A330Y/T438L) on time-scale. (e) Proposed arene oxide pathway of aromatic hydroxylation of 8 catalyzed by P450.

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解析P450催化芳环羟基化反应的机理: 氧化芳烃途径以及区域选择性的探究

Decoding the mechanism of P450-catalyzed aromatic hydroxylation: Uncovering the arene oxide pathway and insights into the regioselectivity

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