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Pyridoxal 5’-phosphate (PLP, vitamin B6) is one of the most ubiquitous cofactors found in biological systems. PLP-dependent enzymes are essential proteins that catalyze a diverse set of reactions: transamination, racemization, phosphorylation, decarboxylation, aldol cleavage, elimination, and oxidation reactions. At least five different fold types comprise the PLP-dependent class of enzymes, each catalyzing a specific chemical reaction. In efforts to develop medicinal and protein engineering applications, researchers have tried for many years to elucidate the underlying physical details that contribute to the reaction diversity among PLP-dependent enzymes. Our working hypothesis is that active site interactions modulate the electronics within the PLP-cofactor to optimize the desired chemical reaction, while significantly decreasing the probability of any unwanted side reactions.