The Energy Landscape of Human Serine Racemase

Human serine racemaseis a pyridoxal5’-phosphate (PLP)-dependent dimeric enzyme that catalyzes the reversible racemization of L- serineand D- serineand their dehydration to pyruvate and ammonia. As D- serineis the co-agonist of the N-methyl D-aspartate receptors for glutamate, the most abundant excitatory neurotransmitter in the brain, the structure, dynamics, function, regulation and cellular localization of serine racemasehave been investigated in detail. Serine racemasebelongs to the fold-type II of the PLP-dependent enzyme family and structural models from several orthologs are available. The comparison of structures of serine racemaseco-crystallized with or without ligands indicates the presence of at least one open and one closed conformation, suggesting that conformational flexibility plays a relevant role in enzyme regulation. ATP, Mg2+, Ca2+, anions, NADH and protein interactors, as well as the post-translational modifications nitrosylationand phosphorylation, finely tune the racemase and dehydrataseactivities and their relative reaction rates. Further information on serine racemasestructure and dynamics resulted from the search for inhibitors with potential therapeutic applications. The cumulative knowledge on human serine racemaseallowed obtaining insights into its conformational landscape and into the mechanisms of cross-talk between the effector binding sites and the active site.