<br>酮还原酶对醛和酮羰基选择性差异的理论分析,Journal of Chemical Information and Modeling

当前位置： X-MOL 学术 › J. Chem. Inf. Model. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

酮还原酶对醛和酮羰基选择性差异的理论分析
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-03-27 , DOI: 10.1021/acs.jcim.3c01996
Ru-De Lin ₁ , Xiu Xing ₁ , Yuan Yu ₁ , Wen-Dian Li _{2,

3} , Dan-Dan Chang _{2,

3} , Fei-Yan Tao _{2,

3} , Na Wang ₁

Affiliation

开菲尔乳杆菌乙醇脱氢酶 ( Lk ADH) 和来自金黄杆菌属的酮还原酶。 CA49 ( Ch KRED12) 对具有酮基和醛羰基的底物表现出不同的化学选择性和立体选择性。 Lk ADH 选择性还原酮羰基，同时保留醛羰基，产生光学纯的R-醇。相比之下， Ch KRED12 选择性还原醛基并对酮羰基表现出较低的反应性。这项研究调查了这些差异的结构基础以及活性位点中特定残基的作用。利用分子动力学（MD）模拟和量子化学计算来研究底物与酶之间的相互作用以及这种现象的根本原因。本研究表明， Lk ADH 和Ch KRED12 在各自活性口袋的结构上表现出显着差异，这是它们对相同底物具有不同化学选择性的关键决定因素。此外， Lk ADH 中的残基 N89、N113 和 E144 以及Ch KRED12 中的 Q151 和 D190 已被确定为通过静电相互作用和范德华力，然后利用辅酶进行氢化物转移，对活性口袋内底物稳定的关键贡献者。 NADPH。此外， Lk ADH 的对映选择性机制已通过量子化学方法得到阐明。总的来说，这些发现不仅为观察到的选择性差异的根本原因提供了基本见解，而且还提供了对催化反应的详细机制理解。

"点击查看英文标题和摘要"

Theoretical Analysis of Selectivity Differences in Ketoreductases toward Aldehyde and Ketone Carbonyl Groups

Lactobacillus kefir alcohol dehydrogenase (LkADH) and ketoreductase from Chryseobacterium sp. CA49 (ChKRED12) exhibit different chemoselectivity and stereoselectivity toward a substrate with both keto and aldehyde carbonyl groups. LkADH selectively reduces the keto carbonyl group while retaining the aldehyde carbonyl group, producing optically pure R-alcohols. In contrast, ChKRED12 selectively reduces the aldehyde group and exhibits low reactivity toward ketone carbonyls. This study investigated the structural basis for these differences and the role of specific residues in the active site. Molecular dynamics (MD) simulations and quantum chemical calculations were used to investigate the interactions between the substrate and the enzymes and the essential cause of this phenomenon. The present study has revealed that LkADH and ChKRED12 exhibit significant differences in the structure of their respective active pockets, which is a crucial determinant of their distinct chemoselectivity toward the same substrate. Moreover, residues N89, N113, and E144 within LkADH as well as Q151 and D190 within ChKRED12 have been identified as key contributors to substrate stabilization within the active pocket through electrostatic interactions and van der Waals forces, followed by hydride transfer utilizing the coenzyme NADPH. Furthermore, the enantioselectivity mechanism of LkADH has been elucidated using quantum chemical methods. Overall, these findings not only provide fundamental insights into the underlying reasons for the observed differences in selectivity but also offer a detailed mechanistic understanding of the catalytic reaction.

更新日期：2024-03-27

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南