Enzymatic Stetter Reaction: Computational Study of the Reaction Mechanism of MenD,ACS Catalysis

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Enzymatic Stetter Reaction: Computational Study of the Reaction Mechanism of MenD
ACS Catalysis ( IF 11.3 ) Pub Date : 2021-09-21 , DOI: 10.1021/acscatal.1c02292
Ferran Planas ₁ , Michael J. McLeish ₂ , Fahmi Himo ₁

Affiliation

Quantum chemical calculations are used to investigate the detailed reaction mechanism of 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylic-acid (SEPHCHC) synthase (also known as MenD), a thiamin diphosphate-dependent decarboxylase that catalyzes the formation of SEPHCHC from 2-ketoglutarate and isochorismate. This enzyme is involved in the menaquinone biosynthesis pathway in M. tuberculosis and is thought of as a potential drug target for anti-tuberculosis therapeutics. In addition, MenD shows promise as a biocatalyst for the synthesis of 1,4-functionalized compounds. Models of the active site are constructed on the basis of available X-ray structures, and the intermediates and transition states involved in the reaction mechanism are optimized and characterized. The calculated mechanism is in good agreement with prior kinetic studies and gives new insights into the mode of action of the enzyme. In particular, the structure and role of the tetrahedral post-decarboxylation intermediate observed in X-ray structures are discussed.

中文翻译：

酶促 Stetter 反应：MenD 反应机理的计算研究

量子化学计算用于研究 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carb-acid (SEPHCHC) 合酶（也称为 MenD）的详细反应机理，这是一种硫胺二磷酸依赖性脱羧酶催化 2-酮戊二酸和异分支酸形成 SEPHCHC。该酶参与结核分枝杆菌的甲基萘醌生物合成途径并且被认为是抗结核治疗的潜在药物靶点。此外，MenD 显示出作为合成 1,4-官能化化合物的生物催化剂的前景。基于现有的X射线结构构建活性位点模型，优化和表征反应机理中涉及的中间体和过渡态。计算出的机制与先前的动力学研究非常一致，并为酶的作用模式提供了新的见解。特别讨论了在 X 射线结构中观察到的四面体脱羧后中间体的结构和作用。

更新日期：2021-10-01

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