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

Ignacio Lizana, Gonzalo A. Jaña, Eduardo J. Delgado

Resultado de la investigación: Article

3 Citas (Scopus)

Resumen

In all ThDP-dependent enzymes, the catalytic cycle is initiated with the attack of the C2 atom of the ylide intermediate on the Cα 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 Cα-C2 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. (Figure Presented).

Idioma originalEnglish
Páginas (desde-hasta)1640-1644
Número de páginas5
PublicaciónJournal of Chemical Information and Modeling
Volumen55
N.º8
DOI
EstadoPublished - 24 ago 2015

Huella dactilar

Pyruvic Acid
Atoms
Molecular Dynamics Simulation
Protons
energy
Potential energy surfaces
Proton transfer
Protonation
Enzymes
Molecular dynamics
activation
Activation energy
Molecules

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences
  • Medicine(all)

Citar esto

@article{fb02d9ea0a40413091e88dacc9cd6c75,
title = "New Insights on the Reaction Pathway Leading to Lactyl-ThDP: A Theoretical Approach",
abstract = "In all ThDP-dependent enzymes, the catalytic cycle is initiated with the attack of the C2 atom of the ylide intermediate on the Cα 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 Cα-C2 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. (Figure Presented).",
author = "Ignacio Lizana and Ja{\~n}a, {Gonzalo A.} and Delgado, {Eduardo J.}",
year = "2015",
month = "8",
day = "24",
doi = "10.1021/acs.jcim.5b00197",
language = "English",
volume = "55",
pages = "1640--1644",
journal = "Journal of Chemical Information and Modeling",
issn = "1549-9596",
publisher = "American Chemical Society",
number = "8",

}

New Insights on the Reaction Pathway Leading to Lactyl-ThDP : A Theoretical Approach. / Lizana, Ignacio; Jaña, Gonzalo A.; Delgado, Eduardo J.

En: Journal of Chemical Information and Modeling, Vol. 55, N.º 8, 24.08.2015, p. 1640-1644.

Resultado de la investigación: Article

TY - JOUR

T1 - New Insights on the Reaction Pathway Leading to Lactyl-ThDP

T2 - A Theoretical Approach

AU - Lizana, Ignacio

AU - Jaña, Gonzalo A.

AU - Delgado, Eduardo J.

PY - 2015/8/24

Y1 - 2015/8/24

N2 - In all ThDP-dependent enzymes, the catalytic cycle is initiated with the attack of the C2 atom of the ylide intermediate on the Cα 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 Cα-C2 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. (Figure Presented).

AB - In all ThDP-dependent enzymes, the catalytic cycle is initiated with the attack of the C2 atom of the ylide intermediate on the Cα 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 Cα-C2 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. (Figure Presented).

UR - http://www.scopus.com/inward/record.url?scp=84940195480&partnerID=8YFLogxK

U2 - 10.1021/acs.jcim.5b00197

DO - 10.1021/acs.jcim.5b00197

M3 - Article

C2 - 26222831

AN - SCOPUS:84940195480

VL - 55

SP - 1640

EP - 1644

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

SN - 1549-9596

IS - 8

ER -