Pyridoxal 5′-phosphate: electrophilic catalyst extraordinaire

Studies of nonenzymatic electrophilic catalysis of carbon deprotonation of glycine show that pyridoxal 5′-phosphate (PLP) strongly enhances the carbon acidity of α-amino acids, but that this is not the overriding mechanistic imperative for cofactor catalysis. Although the fully protonated PLP–glycine iminium ion adduct exhibits an extraordinary low α-imino carbon acidity (p K a = 6), the more weakly acidic zwitterionic iminium ion adduct (p K a = 17) is selected for use in enzymatic reactions. The similar α-imino carbon acidities of the iminium ion adducts of glycine with 5′-deoxypyridoxal and with phenylglyoxylate show that the cofactor pyridine nitrogen plays a relatively minor role in carbanion stabilization. The 5′-phosphodianion group of PLP likely plays an important role in catalysis by providing up to 12 kcal/mol of binding energy that may be utilized for transition state stabilization.