Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0847097 (acidity)
 15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Combined QM/MM simulations have been carried out to investigate the origin of the carbon acidity enhancement in the alanine racemization reaction catalyzed by alanine racemase (AlaR). The present studies show that enhancement of carbon acidity of alpha-amino acids by cofactor pyridoxal 5'-phosphate, PLP, with an unusual, unprotonated pyridine is due to solvation effects, in contrast to the intrinsic electron-withdrawing stabilization by the pyridinium ion to form a quinonoid intermediate. Alanine racemase further lowers the alpha-proton acidity and provides an overall 14-17 kcal/mol transition state stabilization. Our computational results are consistent with the hypothesis that the use of the unusual form of PLP cofactor in AlaR is to raise the free energy of the intermediate, thereby increasing the reprotonation rate and enhancing the enzyme selectivity for racemization.
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PMID:Transition state stabilization and alpha-amino carbon acidity in alanine racemase. 1678 57

Combined quantum mechanical/molecular mechanical simulations have been carried out to investigate the origin of the carbon acidity enhancement in the alanine racemization reaction catalyzed by alanine racemase (AlaR). The present study shows that the enhancement of carbon acidity of alpha-amino acids by the cofactor pyridoxal 5'-phosphate (PLP) with an unusual, unprotonated pyridine is mainly due to solvation effects, in contrast to the intrinsic electron-withdrawing stabilization by the pyridinium ion to form a quinonoid intermediate. Alanine racemase further lowers the alpha-proton acidity and provides an overall 14-17 kcal/mol transition-state stabilization. The second key finding of this study is that the mechanism of racemization of an alanine zwitterion in water is altered from an essentially concerted process to a stepwise reaction by formation of an external aldimine adduct with the PLP cofactor. Finally, we have used a centroid path integral method to determine the intrinsic kinetic isotope effects for the two proton abstraction reactions, which are somewhat greater than the experimental estimates.
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PMID:A combined quantum mechanical and molecular mechanical study of the reaction mechanism and alpha-amino acidity in alanine racemase. 1716 90