Transition state structures for the molecular mechanism of lactate dehydrogenase enzyme

Abstract

The possible reaction pathways of the molecular mechanisms for the transformation from pyruvate to lactate in the active site of the lactate dehydrogenase (LDH) enzyme have been characterized by means of the PM3 and AM1 semiempirical methods. The energies and optimized geometries of the stationary points have been calculated on the potential energy surface. Medium effects have been estimated by means of AMSOL calculations.

Both PM3 and AM1 methods indicate that the transition state structure that controls the overall process is dominated by the hydride transfer from nicotinamide adenine dinucleotide to the pyruvate carbonyl carbon. The transition vector and the reaction pathways show that the hydride and proton transfers are kinetically coupled but dynamically uncoupled.

The AM1 and PM3 results can be summarized as follows: (i) there are differences in the representation of the interaction associated with proton transfer from the imidazole ring to the pyruvate carbonyl oxygen and the substrate fixation controlled by weak H–bonds between pyruvate and a guanidine residue, and (ii)ab initio and PM3 results fulfil the principle of maximum overlap of HOMO-LUMO for hydride–transfer reactions for this and related reactions.