STEREOCHEMICAL CONSTRAINT IN THE EVOLUTION OF PYRIDOXAL-5'-PHOSPHATE-DEPENDENT ENZYMES - A HYPOTHESIS

In the transamination reactions undergone by pyridoxal-5'-phosphate-de pendent enzymes that act on L-amino acids, the C4' atom of the cofacto r is without exception protonated from the si side. This invariant abs olute stereochemistry of enzymes not all of which are evolutionarily r elated to each other and the inverse stereochemistry in the case of D- alanine aminotransferase might reflect a stereochemical constraint in the evolution of these enzymes rather than an accidental historical tr ait passed on from a common ancestor enzyme. Conceivably, the coenzyme and substrate binding sites of primordial pyridoxal-5'-phosphate-depe ndent enzymes had to fulfil the following prerequisites in order to al low their development toward effective catalysts: (i) the negatively c harged alpha-carboxylate group of the amino acid substrate had to be p ositioned as far as possible away from the negatively charged phosphat e group of the cofactor, and (ii) the C alpha-H bond had to be oriente d toward the protein. Compliance with these two criteria implies, unde r the assumption that C4' is protonated by an acid-base group of the p rotein, the observed stereochemical feature.