News Release

Coordination dynamics of iron enables the selective C-N coupling but bypasses unwanted C-H hydroxylation in Fe(II)/-ketoglutarate-dependent non-heme enzymes

Peer-Reviewed Publication

Dalian Institute of Chemical Physics, Chinese Academy Sciences

Figure Abstract

image: 

The mechanisms for the TqaLNC-catalyzed aziridine formation involve: (1) conformational change of the Fe(IV)=O species from the axial one to the equatorial one; (2) the deprotonation of the substrate NH3+ group to form the NH-ligated intermediate; (3) the C-H activation by the equatorial Fe(IV)=O species and (4) the final C-N coupling within the Fe-ligated substrate radical intermediate. The steric effects and the frontier orbitals are vital in dictating the aziridination but bypassing the unwanted hydroxylation.

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Credit: Chinese Journal of Catalysis

Aziridine is a key functional group that is presented in natural products. Due to its inherent ring strain, aziridine displays remarkable reactivity in targeting and disrupting the DNA bases of cancer cells through the nucleophilic attack reactivity. In nature, many aziridine-bearing compounds have been isolated from fungi, actinomycetes and marine sponges. However, the biosynthetic mechanisms for these natural compounds are elusive.

TqaLNC, a member of Fe(II)/a-ketoglutarate (aKG)-dependent oxygenase that is characterized recently, catalyzes the oxidative C-N bond formation from L-valine (L-Val). However, how this enzyme dictates the generation of the high-energy three-membered ring and simultaneously inhibits the unwanted hydroxylation reaction is an intriguing issue.

Recently, a research team led by Prof. Binju Wang from Xiamen University, China, have conducted extensive MD simulations and QM/MM calculations on several systems of TqaLNC, including: (1) substrate L-Val with TqaLNc; (2) substrate L-Ile with TqaLNc; (3) substrate L-Ile with F345A-TqaLNc; (4) substrate L-homoalanine with TqaLNc. The computational results reveal that both the conformational isomerization of Fe(IV)=O and the substrate coordination are key to the selective C-N coupling by TqaLNc. Such mechanistic scenario has been cross-validated by oxidation of various substrate by TqaLNc and its variants. In addition, the selectivity partition between the aziridination vs. hydroxylation is controlled by the frontier orbitals and steric effects. The results were published in Chinese Journal of Catalysis (https://doi.org/10.1016/S1872-2067(24)60064-1).

Computational studies have shown that the aziridine formation involves (1) conformational change of the Fe(IV)=O species from the axial configuration to the equatorial one, (2) deprotonation of the substrate NH3+ group to form the NH-ligated intermediate, (3) C-H activation by the equatorial Fe(IV)=O species and (4) the final C-N coupling within the Fe-ligated substrate radical intermediate. Especially, both the conformational change of Fe(IV)=O species and the substrate coordination are key to the selective C-N coupling, which are unexpected in catalysis of most non-heme enzymes.

The frontier orbitals and steric effects are the key determinants for the selectivity partition. It was demonstrated that the intrinsic reactivity of aziridination vs. hydroxylation is dictated by the energy splitting between two key redox-active dπ* frontier molecular orbitals: dπ*Fe-N and dπ*Fe-OH. Furthermore, as the aziridination reaction involves the significant rotation of the side-chain of the substrate, the presence of steric hindrance between the substrate and the second-sphere residues would largely inhibit the aziridination and thereby elevate its barrier. Unlike the aziridination, the steric hindrance has minor effects on the OH-rebound step. Consequently, the strong steric hindrance led to the preference of the hydroxylation, while the weak steric hindrance led to the preference of aziridination. These insights can expand our understanding on the catalysis of the superfamily of Fe(II)/aKG-dependent enzymes.

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About the Journal

Chinese Journal of Catalysis is co-sponsored by Dalian Institute of Chemical Physics, Chinese Academy of Sciences and Chinese Chemical Society, and it is currently published by Elsevier group. This monthly journal publishes in English timely contributions of original and rigorously reviewed manuscripts covering all areas of catalysis. The journal publishes Reviews, Accounts, Communications, Articles, Highlights, Perspectives, and Viewpoints of highly scientific values that help understanding and defining of new concepts in both fundamental issues and practical applications of catalysis. Chinese Journal of Catalysis ranks among the top one journals in Applied Chemistry with a current SCI impact factor of 15.7. The Editors-in-Chief are Profs. Can Li and Tao Zhang.

At Elsevier http://www.journals.elsevier.com/chinese-journal-of-catalysis

Manuscript submission https://mc03.manuscriptcentral.com/cjcatal


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