This study reports the carbon acidities of C alpha and C4' atoms in the Schiff bases of pyridoxal-5'-phosphate (PLP) and pyridoxamine-5'-phosphate (PMP) complexed with several biologically available metal ions (Me2+, Ni2+, Zn2+, Cu2+, Al3+, and Fe3+). Density functional theory calculations were carried out to determine the free energies of proton exchange reactions of a set of 18 carbon acids and a Schiff base used as a reference species. The experimental pK(a) values of such carbon acids were used to calibrate the computed free energies in a range of 30 pK(a) units. Eventually, the pK(a)s of the chelates were obtained by calculating the corresponding free energies against the same reference species and by considering the previous calibration. The carbon acidity of C alpha in the chelates of Mg2+, Ni2+, Zn2+, and Cu2+ varies between pK(a) similar to 22 and pK(a) similar to 13 whereas the pK(a) values of C4' range between similar to 18 and similar to 7. Chelation of trivalent metals Al3+ and Fe3+ causes further decrease of the pK(a) values of C alpha and C4' down to similar to 10 and similar to 5, respectively. The results highlight the efficiency of the combined action of Schiff base formation and metal chelation to activate the C alpha carbon of amino acids (pK(a) similar to 29 for zwitterionic alanine). Our results explain that the experimental increase of transamination rates by Zn2+ chelation is due to stabilization of the reactive Schiff base species with respect to the free ligand under physiological pH conditions. However, the increase in reactivity for transamination due to Cu2+ and Al3+ chelation is mostly due to C-H ligand activation. Each metal ion activates the C alpha and C4' carbon atoms to a different extent, which can be exploited to favor specific reactions on the amino acids in aqueous solution. Metal chelation hinders both intramolecular and intermolecular proton-transfer reactions of the imino, phenol, and carboxylate groups. This is the only apparent inconvenience of metal complexes in enzymatic reactions, which, in turn, proposes their consideration for enzyme inhibition.