Reduction of 伪,尾-Unsaturated Ketones by Old Yellow Enzymes: Mechanistic Insights from Quantum Mechanics/Molecular Mechanics Calculations

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• 作者：Richard Lonsdale ; Manfred T. Reetz
• 刊名：Journal of the American Chemical Society
• 出版年：2015
• 出版时间：November 25, 2015
• 年：2015
• 卷：137
• 期：46
• 页码：14733-14742
• 全文大小：587K
• ISSN：1520-5126

文摘

Enoate reductases catalyze the reduction of activated C鈺怌 bonds with high enantioselectivity. The oxidative half-reaction, which involves the addition of a hydride and a proton to opposite faces of the C鈺怌 bond, has been studied for the first time by hybrid quantum mechanics/molecular mechanics (QM/MM). The reduction of 2-cyclohexen-1-one by YqjM from Bacillus subtilis was selected as the model system. Two-dimensional QM/MM (B3LYP-D/OPLS2005) reaction pathways suggest that the hydride and proton are added as distinct steps, with the former step preceding the latter. Furthermore, we present interesting insights into the reactivity of this enzyme, including the weak binding of the substrate in the active site, the role of the two active site histidine residues for polarization of the substrate C鈺怬 bond, structural details of the transition states to hydride and proton transfer, and the role of Tyr196 as proton donor. The information presented here will be useful for the future design of enantioselective YqjM mutants for other substrates.