Fe(II)/α-KG依赖型双加氧酶NvfI催化内过氧化物形成: 底物介导远端C-H键活化与双氧分子插入机制研究

doi:10.1016/S1872-2067(26)64954-6

催化学报 ›› 2026, Vol. 82: 363-377.DOI: 10.1016/S1872-2067(26)64954-6

• 论文 • 上一篇

Fe(II)/α-KG依赖型双加氧酶NvfI催化内过氧化物形成: 底物介导远端C-H键活化与双氧分子插入机制研究

余俊^a, 付玉状^b^,^a, 王斌举^a^,^*(), 曹泽星^a^,^*()

^a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
^b中国药科大学中药学院, 多靶标天然药物全国重点实验室, 江苏南京 210009

收稿日期:2025-07-04 接受日期:2025-10-21 出版日期:2026-03-18 发布日期:2026-03-05
通讯作者: * 电子信箱: wangbinju2018@xmu.edu.cn (王斌举),zxcao@xmu.edu.cn (曹泽星).
基金资助:
国家自然科学基金(22373078);国家自然科学基金(21933009);国家自然科学基金(22122305)

Enzymatic formation of endoperoxide by Fe(II)/α-KG-dependent dioxygenase NvfI: Insight into substrate-assisted activation of the distant C-H bond and incorporation of two oxygen molecules

Jun Yu^a, Yuzhuang Fu^b^,^a, Binju Wang^a^,^*(), Zexing Cao^a^,^*()

^aState 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, Xiamen 361005, Fujian, China
^bDepartment of Resources Science of Traditional Chinese Medicines, School of Traditional Chinese Pharmacy, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China

Received:2025-07-04 Accepted:2025-10-21 Online:2026-03-18 Published:2026-03-05
Contact: * E-mail: wangbinju2018@xmu.edu.cn (B. Wang),zxcao@xmu.edu.cn (Z. Cao).
Supported by:
Natural Science Foundation of China(22373078);Natural Science Foundation of China(21933009);Natural Science Foundation of China(22122305)

摘要/Abstract

摘要：

非血红素Fe(II)/2OG依赖型氧化酶是一类多功能金属酶, 在复杂天然产物的生物合成中, 该类酶能催化引入多种关键官能团, 发挥着至关重要的作用. 本文研究的双加氧酶NvfI能够活化底物远端的C-H键, 进而引发底物的内环氧化和羟基化反应, 生成具有潜在抗肿瘤等药用价值的产物. 与催化近端C-H键活化的非血红素加氧酶不同, 目前关于NvfI酶催化底物的机理研究尚不充分, 其远端C-H键选择性活化与氧化的分子机制仍不清楚, 有待深入解析. 因此, 本研究通过系统的多尺度理论模拟, 从原子/分子层面完整揭示了NvfI催化生成内过氧化合物的反应机制.

本文利用分子动力学(MD)和量子力学/分子力学(QM/MM)组合方法, 系统地研究了Fe(II)/2OG依赖型双加氧酶NvfI催化合成内过氧化合物的反应机制: 包括Fe(IV)-oxo活性物种的形成、C13号位底物自由基的形成、第二个氧分子的引入与产物的形成. 首先, 通过MD模拟, 得到了酶-底物-氧分子三元复合物的稳定结构. 基于稳定结构, 随后的QM/MM计算确定了关键活性中间体Fe(IV)-oxo生成过程以及势能面. 后续QM/MM计算表明新生成的Fe(IV)-oxo活性物种无法直接攫取底物远端C13位置的氢原子, 而是会优先攫取较近的底物C7′位点的氢原子. 随后通过底物分子内的氢原子转移过程, 获得在C13号位底物自由基物种, 对应的能垒为8 kcal/mol. 而羟基反弹至底物的C7′号位生成羟基化产物的能垒为10.2 kcal/mol, 这与实验中观测到C7′号位羟基化产物为副产物的结果一致. 随着第二分子的氧气进入酶的活性中心, 其能够与底物自由基发生偶联并在C3′号位形成具有自由基特征的内环氧化中间体. 最终, 在酶活性中心残基的动态重排的驱动下, 羟基回弹至底物的C3′号位从而形成最终产物, 值得注意的是, 在HAT和羟基回弹机制中, 第二壳层的残基发挥着关键的稳定和促进作用.

综上, 本工作提出了底物协助的两次连续氢原子转移过程实现远端的C-H键活化的机制, 揭示了Fe(II)/2OG依赖性双加氧酶NvfI形成内过氧化物的酶催化机理. 为理解这类非血红素Fe(II)/2OG依赖型氧化酶活化底物远端C-H键提供了新的视角, 也对后续的酶改造和酶工程具有参考意义.

关键词: Fe/2OG依赖型双加氧酶, 量子力学/分子力学, 氧气活化, 氢原子转移, 内过氧化合物

Abstract:

NvfI, a 2-oxoglutarate (2OG)-dependent non-heme Fe(II) dioxygenase, catalyzes the formation of endoperoxide-containing fumigatonoid A, a key step in the biosynthesis of novofumigatonin. However, the molecular mechanism underlying these processes remains elusive. To address this, extensive MD simulations and QM/MM calculations were performed. Our computational study suggests that the nascent Fe(IV)-oxo species is not able to conduct the H-abstraction from the target C13-H directly. Instead, the Fe(IV)-oxo species performs the H-abstraction from the proximal C7′-H, and the resulting C7′-centered radical can serve as the radical relay for the further oxidation of the distal C13-H bond. Such radical relay mechanism not only remarkably reduces the barrier for the activation of the distal C13-H bond, but also efficiently prevents the undesired OH-rebound pathway. Regarding the final OH-rebound at the C3′ site, our study suggests that the dynamic reorganization of the active site reduces the distance between the substrate radical and the Fe(III)-OH, facilitating the efficient OH-rebound at the C3′ site. These computational findings offer valuable insights for NvfI-catalyzed biosynthesis of endoperoxide.

Key words: Fe/2OG-dependent dioxygenase, Quantum mechanical/molecular mechanical, Dioxygen activation, Hydrogen atom transfer, Endoperoxide

余俊, 付玉状, 王斌举, 曹泽星. Fe(II)/α-KG依赖型双加氧酶NvfI催化内过氧化物形成: 底物介导远端C-H键活化与双氧分子插入机制研究[J]. 催化学报, 2026, 82: 363-377.

Jun Yu, Yuzhuang Fu, Binju Wang, Zexing Cao. Enzymatic formation of endoperoxide by Fe(II)/α-KG-dependent dioxygenase NvfI: Insight into substrate-assisted activation of the distant C-H bond and incorporation of two oxygen molecules[J]. Chinese Journal of Catalysis, 2026, 82: 363-377.

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https://www.cjcatal.com/CN/Y2026/V82/I3/363

图/表 11

Scheme 1. (a) The typical pathways for the formation of the ferryl-oxo species in the Fe/2OG-dependent dioxygenases. (b) The production of fumigatonoid A (2) from asnovolin A (1) catalyzed by NvfI in the biosynthesis of novofumigatonin.

Fig. 1. The overall structure of enzyme (NvfI)-substrate (Sub) complex (PDB ID: 7DE2), and the active site structure of NvfI. The element C of substrate is colored in cyan blue, while the rest of elements C, N, O, Fe are colored in green, blue, red and orange, respectively.

Fig. 2. The QM(UB3LYP/B2)/MM predicted relative energy (in kcal/mol) and corresponding structures of different spin states (triplet, quintet and septet) in RC, the septet is calculated to be the ground state, and is set as the reference point of 0.0 kcal/mol. The spin density(ρ) of key atoms are presented in the bottom right corner.

Fig. 3. The QM (UB3LYP-D3/def2-TZVP)/MM predicted relative energy profile (kcal/mol) and QM(UB3LYP-D3/def2-SVP)/MM-optimized structures of key species involved in the formation of the ferryl-oxo species are provided. The distances are given in ?, and the spin density (ρ) of key atoms are presented in the bottom right corner. The dispersion corrections and ZPEs are included in the relative energies and optimized geometries of key species involved in the reaction. The spin states of Fe are determined to be S = 5/2 for species RC and IM2, and S = 2 for IM1, IM3, IM3′ and IM4.

Fig. 4. The evolution of distances between O@ferryl-oxo and C7′@substrate (labeled in R1) and C13@substrate (labeled in R2) during the 2.0 ps QM/MM MD simulations.

Fig. 5. The QM (UB3LYP-D3/def2-TZVP)/MM predicted relative energies (kcal/mol) for the HAT and hydroxyl group rebound reactions. And the QM(UB3LYP-D3/def2-SVP)/MM optimized structures of key species are provided. The distances are given in ? and the spin density (ρ) of key atoms is presented in the bottom right corner. The dispersion corrections and ZPEs are included in the relative energies and optimized geometries of key species involved in the reaction. The spin states of Fe are determined to be S = 2 for species IM4 and IM6*, and S = 5/2 for IM5 and IM6.

Fig. 6. Electron-shifting diagram for the radical relay and hydroxyl group rebound reactions.

Fig. 7. Four parallel MM MD simulations. (a) The overlap of the most representative structures of four MD simulations. (b) The probability of a water molecule being present within the active site during the last 100 ns of MD simulations trajectories. (c) The distance (in ?) between the C3′ of substrate and the OH group of Fe(III)-OH during the last 100 ns of MD simulations trajectories. (d) The distance (in ?) between the C13 of substrate and the center of mass of dioxygen during the last 100 ns of MD simulations trajectories.

Fig. 8. The QM (UB3LYP-D3/def2-TZVP)/MM predicted relative energies (kcal/mol) for the formation of the IM9 on the septet PES (black) and quintet PES (red). And the QM(UB3LYP-D3/def2-SVP)/MM optimized structures of key species are provided. The distances are given in ? and the spin densities (ρ) of key atoms are presented in the bottom right corner. The dispersion corrections and ZPEs are included in the relative energies and optimized geometries of key species involved in the reaction. The spin states of Fe are determined to be S = 5/2 for species IM6′, IM7, IM8 and IM9.

Scheme 2. The mechanism for NvfI-catalyzed endoperoxide formation reaction.

Fig. 9. (a) The QM (UB3LYP-D3/def2-TZVP)/MM predicted relative energies (kcal/mol) for the water-assisted rebound reaction. And the QM(UB3LYP-D3/def2-SVP)/MM optimized structures of key species are provided. The distances are given in ? and the spin densities (ρ) of key atoms are presented in the bottom right corner. The dispersion corrections and ZPEs are included in the relative energies and optimized geometries of key species involved in the reaction. (b) The representative structure (IM9′) from 200 ns MM MD simulations conducted for species IM9 and QM/MM optimized structure (PC′), where the distances are given in ? and the spin densities (ρ) of key atoms are presented in the bottom right corner. The spin states of Fe are determined to be S = 5/2 for species IM9′ and S = 2 for species PC.

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Fe(II)/α-KG依赖型双加氧酶NvfI催化内过氧化物形成: 底物介导远端C-H键活化与双氧分子插入机制研究

Enzymatic formation of endoperoxide by Fe(II)/α-KG-dependent dioxygenase NvfI: Insight into substrate-assisted activation of the distant C-H bond and incorporation of two oxygen molecules

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