New Insights on the Reaction Pathway Leading to Lactyl-ThDP: A Theoretical Approach

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• 作者：Ignacio Lizana ; Gonzalo A. Ja帽a ; Eduardo J. Delgado
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2015
• 出版时间：August 24, 2015
• 年：2015
• 卷：55
• 期：8
• 页码：1640-1644
• 全文大小：291K
• ISSN：1549-960X

文摘

In all ThDP-dependent enzymes, the catalytic cycle is initiated with the attack of the C₂ atom of the ylide intermediate on the C_伪 atom of a pyruvate molecule to form the lactyl-ThDP (L-ThDP) intermediate. In this study, the reaction between the ylide intermediate and pyruvate leading to the formation of L-ThDP is addressed from a theoretical point of view. The study includes molecular dynamics, exploration of the potential energy surface by means of QM/MM calculations, and reactivity analysis on key centers. The results show that the reaction occurs via a concerted mechanism in which the carboligation and the proton transfers occur synchronically. It is also observed that during the reaction the protonation state of the N1鈥?atom changes: the reaction starts with the ylide having the N1鈥?atom deprotonated and reaches a transition state showing the N1鈥?atom protonated. This conversion leads to the reaction path of minimum energy, with an activation energy of about 20 kcal mol^鈥?. On the other hand, it is also observed that the approaching distance between the pyruvate and the ylide, i.e., the C_伪鈥揅₂ distance, plays a fundamental role in the reaction mechanism since it determines the nucleophilic character of key atoms of the ylide, which in turn trigger the elemental reactions of the mechanism.