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

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

Abstract

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

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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URL: https://www.cjcatal.com/EN/10.1016/S1872-2067(26)64954-6

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

Figures/Tables 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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