Abstract
Human serine racemase is a pyridoxal 5′-phosphate (PLP)-dependent dimeric enzyme that catalyzes the reversible racemization of L-serine and D-serine and their dehydration to pyruvate and ammonia. As D-serine is 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 racemase have been investigated in detail. Serine racemase belongs 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 racemase co-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 nitrosylation and phosphorylation, finely tune the racemase and dehydratase activities and their relative reaction rates. Further information on serine racemase structure and dynamics resulted from the search for inhibitors with potential therapeutic applications. The cumulative knowledge on human serine racemase allowed obtaining insights into its conformational landscape and into the mechanisms of cross-talk between the effector binding sites and the active site.
Highlights
The N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels involved in synapse formation, synaptic plasticity, learning and memory potentiation (Paoletti et al, 2013)
This site is not directly involved in catalysis, it is connected through water molecules to a tetra-glycine loop (Gly 183-184185-186 for Schizosaccharomyces pombe SR (SpSR) and 185-186-187-188 for rat SR (rSR) and human SR (hSR)) at the N-terminal of α-helix H9, which forms a series of H-bonds with the phosphate group of pyridoxal 5′-phosphate (PLP), contributing to the correct positioning of the cofactor
In addition to small molecule effectors and post-translational modifications, Serine racemase (SR) function is regulated by the interaction with specific proteins, proteins associated with AMPA and NMDA receptors
Summary
Samanta Raboni 1, Marialaura Marchetti 2, Serena Faggiano 1,3, Barbara Campanini 1, Stefano Bruno 1, Francesco Marchesani 1, Marilena Margiotta 1 and Andrea Mozzarelli 1,3,4*. The Energy Landscape of Human Serine Racemase. Human serine racemase is a pyridoxal 5′-phosphate (PLP)-dependent dimeric enzyme that catalyzes the reversible racemization of L-serine and D-serine and their dehydration to pyruvate and ammonia. Serine racemase belongs 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 racemase co-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. Further information on serine racemase structure and dynamics resulted from the search for inhibitors with potential therapeutic applications. The cumulative knowledge on human serine racemase allowed obtaining insights into its conformational landscape and into the mechanisms of cross-talk between the effector binding sites and the active site
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