The role of the pyridoxyl functionality on pyridoxal 5'-phosphate (PLP)-dependent enzymatic decarboxylation of or-amino acids has been examined using ab initio calculations at electron-correlated levels of theory (MP2/6-31G(d) and B3LYP/6-31G(d)), The zwitterionic reactant intermediates involved are used to measure the effects of ground-state destabilization on the activation barriers. Inclusion of the 2-hydroxy-3-methylpyridine group, as in alanine imine with PLP (5), results in a decrease in the barrier height to 20.1 kcal/mol. Either an intramolecular 1,4-proton shift from the carboxylic acid group or general acid catalysis by the phenol group in 5 affords a protonated aldimine group that provides Coulombic stabilization for the decarboxylation step (TS-6 and TS-7). There is no change in electron density of the pyridoxyl ring in either neutral transition structure. The "electron sink" effect attributed to the amide functionality in pyruvoyl-dependent and the pyridoxyl group in PLP-dependent decarboxylation is absent. The barrier heights of the pyruvoyl-dependent (TS-3) and PLP-dependent (TS-7) decarboxylations are quite similar. The three pertinent structural features essential to efficient PLP-dependent decarboxylation are (i) the Coulombic influence of proton transfer to the imine nitrogen in the transition state for decarboxylation, (ii) the short, strong stabilizing hydrogen bond of the phenol oxygen anion with the imine hydrogen in the transition structure, and (iii) the formation of zwitterionic intermediates along the reaction coordinate with an energy-compensating Coulombic stabilization of the PLP cofactor at the active sire. In decarboxylation reactions involving salt bridges, the potential for an increase in distance between oppositely charged centers must be alleviated early along the reaction coordinate by annihilation of the salt bridge to avoid marked increases in energy.