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α,β-不饱和脂肪酸的意外反应揭示了CYP152过氧酶机制
作者:小柯机器人 发布时间:2021/9/16 15:38:22

山东大学李盛英团队报道了α,β-不饱和脂肪酸的意外反应揭示了CYP152过氧酶机制。相关研究成果于2021年9月15日发表于国际顶尖学术期刊《德国应用化学》。

CYP152过氧酶使用H2O2作为辅助因子催化脂肪酸的脱羧和羟基化。

为了了解这些独特的P450酶化学选择性和区域选择性的分子基础,该文中,研究人员分析了三种具有代表性的CYP152过氧酶(OleTJE、P450SPα和P450BSβ)对顺式和反式十二烯酸作为底物探针的活性。OleTJE对反式异构体的意外6S羟基化和顺式异构体的4R羟基化以及分子对接结果表明,前所未有的选择性可能是由于OleTJE偏好C2-C3顺式构型。

更令人惊讶的是,除了常见的环氧化物产物外,无论底物的顺/反构型如何,十一烷醇都是P450SPα和P450BSβ的意外主要产物。结合同位素标记的H218O2示踪实验、MD模拟和QM/MM计算,揭示了化合物I介导的醛形成的不寻常机制,其中来自H2O2活化的活性位点水参与了四元环内酯中间体的生成。该发现为CYP152过氧酶的异常机制提供了新的见解。

附:英文原文

Title: Unexpected Reactions of α,β-Unsaturated Fatty Acids Provide Insight into the Mechanisms of CYP152 Peroxygenases

Author: Yuanyuan Jiang, Wei Peng, Zhong Li, Cai You, Yue Zhao, Dandan Tang, Binju Wang, Shengying Li

Issue&Volume: 2021-09-15

Abstract: CYP152 peroxygenases catalyze decarboxylation and hydroxylation of fatty acids using H2O2   as cofactor. To understand the molecular basis for the chemo- and regioselectivity of these unique P450 enzymes, herein, we analyze the activities of three representative CYP152 peroxygenases (OleTJE, P450SPα  and P450BSβ) towards  cis- and  trans-dodecenoic acids as substrate probes. The unexpected 6S-hydroxylation of the  trans-isomer and 4R-hydroxylation of the  cis-isomer by OleTJE, and molecular docking results suggest that the unprecedented selectivity is likely due to OleTJE's preference of C2-C3  cis-configuration. More surprisingly, in addition to the common epoxide products, undecanal is the unexpected major product of P450SPα  and P450BSβ  regardless the  cis/trans-configuration of substrates. The combined isotopically-labeled H218O2  tracing experiments, MD simulations and QM/MM calculations unravel an unusual mechanism for Compound I-mediated aldehyde formation, in which the active site water derived from H2O2  activation is involved in the generation of a four-membered ring lactone intermediate. These findings provide new insights into the unusual mechanisms of CYP152 peroxygenases.

DOI: 10.1002/anie.202111163

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202111163

期刊信息

Angewandte Chemie:《德国应用化学》,创刊于1887年。隶属于德国化学会,最新IF:12.959
官方网址:https://onlinelibrary.wiley.com/journal/15213773
投稿链接:https://www.editorialmanager.com/anie/default.aspx