期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 55, 期 8, 页码 1640-1644出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.5b00197
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类别
资金
- Grant Fondecyt [1130082]
- Doctoral Network UCO [1202]
In all ThDP-dependent enzymes, the catalytic cycle is initiated with the attack of the C-2, atom of the ylide intermediate on the C-alpha 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' atom changes: the reaction starts with the ylide having the N1' atom deprotonated and reaches a transition state showing the N1' atom protonated. This conversion leads to the reaction path of minimum energy, with an activation energy of about 20 kcal mol(-1). On the other hand, it is also observed that the approaching distance between the pyruvate and the ylide, i.e., the C-alpha-C-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.
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