TRANSITION-STATE STRUCTURES FOR THE MOLECULAR MECHANISM OF LACTATE-DEHYDROGENASE ENZYME

The possible reaction pathways of the molecular mechanisms for the tra nsformation from pyruvate to lactate in the active;site of the lactate dehydrogenase (LDH) enzyme have been characterized by means of the PM 3 and AM 1 semiempirical methods. The energies and optimized geometrie s of the stationary:points have been calculated on the potential energ y surface. Medium effects have been estimated by means of AMSOL calcul ations. Both PM3 and AM1 methods indicate that the transition state st ructure that controls the overall process is dominated by the hydride transfer from nicotinamide adenine dinucleotide to the pyruvate carbon yl carbon. The transition vector and the reaction pathways show that t he hydride and proton transfers are kinetically coupled but dynamicall y uncoupled. The AM1 and PM3 results can be summarized as follows: (i) there are differences in the representation of the interaction associ ated with proton transfer from the imidazole ring to the pyruvate carb onyl oxygen and the substrate fixation controlled by weak H-bonds betw een pyruvate and a guanidine residue; and (ii) ab initio and PM3 resul ts fulfil the principle of maximum overlap of HOMO-LUMO for hydride-tr ansfer reactions for this and related reactions.