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Computational determination of fundamental pathway and activation barriers for acetohydroxyacid synthase‐catalyzed condensation reactions of α‐keto acids
Author(s) -
Xiong Ying,
Liu Junjun,
Yang GuangFu,
Zhan ChangGuo
Publication year - 2010
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.21356
Subject(s) - chemistry , catalysis , transition state , hydrogen bond , combinatorial chemistry , enzyme catalysis , cofactor , condensation reaction , active site , stereochemistry , computational chemistry , amino acid , enzyme , molecule , organic chemistry , biochemistry
Acetohydroxyacid synthase (AHAS) is the first common enzyme in the biosynthetic pathway leading to the production of various branched‐chain amino acids. AHAS is recognized as a promising target for new antituberculosis drugs, antibacterial drugs, and herbicides. Extensive first‐principles quantum mechanical (QM) and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations have enabled us, in this study, to uncover the fundamental reaction pathway, determine the activation barriers, and obtain valuable insights concerning the specific roles of key amino acid residues for the common steps of AHAS‐catalyzed condensation reactions of α‐keto acids. The computational results reveal that the rate‐determining step of the AHAS‐catalyzed reactions is the second reaction step and that the most important amino acid residues involved in the catalysis include Glu144′, Gln207′, Gly121′, and Gly511 that form favorable hydrogen bonds with the reaction center (consisting of atoms from the substrate and cofactor) during the reaction process. In addition, Glu144′ also accepts a proton from cofactor thiamin diphosphate (ThDP) through hydrogen bonding during the catalytic reaction. The favorable interactions between the reaction center and protein environment remarkably stabilize the transition state and, thus, lower the activation barrier for the rate‐determining reaction step by ∼20 kcal/mol. The activation barrier calculated for the rate‐determining step is in good agreement with the experimental activation barrier. The detailed structural and mechanistic insights should be valuable for rational design of novel, potent AHAS inhibitors that may be used as promising new anti‐tuberculosis drugs, antibacterial drugs, and/or herbicides to overcome drug resistance problem. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010