A Cytochrome P450 TxtE Model System with Mechanistic and Theoretical Evidence for a Heme Peroxynitrite Active Species

过氧亚硝酸盐 硝化作用 化学 血红素 细胞色素P450 色氨酸 区域选择性 血红素蛋白 活动站点 部分 立体化学 组合化学 生物化学 有机化学 超氧化物 催化作用 氨基酸
作者
Pritam Mondal,Dhilanka Udukalage,Abubaker A. Mohamed,Henrik P. H. Wong,Sam P. de Visser,Gayan B. Wijeratne
出处
期刊:Angewandte Chemie [Wiley]
标识
DOI:10.1002/anie.202409430
摘要

The cytochrome P450 homolog, TxtE, efficiently catalyzes the direct and regioselective aromatic nitration of the indolyl moiety of L‐tryptophan to 4‐nitro‐L‐tryptophan, using nitric oxide and dioxygen as co‐substrates. Pathways for such direct and selective nitration of heteroaromatic motifs present platforms for engineering new nitration biocatalysts for pharmacologically beneficial targets, among a medley of other pivotal industrial applications. Precise mechanistic details concerning this pathway are only weakly understood, albeit a heme iron(III)‐peroxynitrite active species has been postulated. To shed light on this unique reaction landscape, we investigated the indole nitration pathway of a series of biomimetic ferric heme superoxide mimics, [(Por)FeIII(O2–•)], in the presence of NO. Therein, our model systems gave rise to three distinct nitroindole products, including 4‐nitroindole, the product analogous to that obtained with TxtE. Moreover, 15N and 18O isotope labeling studies, along with meticulously designed control experiments lend credence to a heme peroxynitrite active nitrating agent, drawing close similarities to the tryptophan nitration mechanism of TxtE. All organic and inorganic reaction components have been fully characterized using spectroscopic methods. Theoretical investigation into several mechanistic possibilities deem a unique indolyl radical based reaction pathway as the most energetically favorable, products of which, are in excellent agreement with experimental findings.
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