A combined quantum mechanical and molecular mechanical study of the reaction mechanism and α-amino acidity in alanine racemase

Dan Thomas Major, Jiali Gao

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110 Scopus citations

Abstract

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 α-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 α-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.

Original languageEnglish (US)
Pages (from-to)16345-16357
Number of pages13
JournalJournal of the American Chemical Society
Volume128
Issue number50
DOIs
StatePublished - Dec 20 2006

Bibliographical note

Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.

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