The Energy Landscape of Human Serine Racemase

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.

D-serine mitigates cell loss associated with temporal lobe epilepsy

“…Astrocytes, like neurons, are a putative source of D-serine in the brain (express serine racemase, the enzyme that converts L- to D-serine) 16 , 17 and therefore capable of regulating endogenous levels within MEA. Hence, we asked if their numbers and/or reactive status were also affected by TLE 18 .…”

d-amino Acids in Health and Disease: A Focus on Cancer

“…Currently, two racemase enzymes have been found in mammals: serine racemase and aspartate racemase [20]. Of these two enzymes, only serine racemase has been found in human tissue [21,22,23]. The presence of aspartate racemase, on the other hand, has been detected in mice, amphibians, mollusks, and bacterial species [20,24].…”

Tyrosine 121 moves revealing a druggable pocket that couples catalysis to ATP-binding in serine racemase

“…In all hSR structures, the Mn 2+ , Mg 2+ or Ca 2+ ions are similarly octahedrally coordinated by the main chain carbonyl of Ala 214, the side chains of Glu 210 and Asp 216, and three water molecules. Two of the three waters donate hydrogen bonds to backbone carbonyls where the corresponding main-chain NHs (from the tetra-glycine loop Gly 185-188 in hSR) donate H-bonds to the phosphate group of PLP 39 , thus helping organise the PLP binding site. The Mg 2+ ion coordinated the β and γ phosphates of ATP is also coordinated by four waters that make up a standard octahedral coordination sphere.…”

“…Both the racemisation and elimination reactions of SR are activated to some degree by ATP, but not identically in mammals and yeast. The activating effect of ATP can be potentiated by the divalent cations Mg 2+ , Mn 2+ , and Ca 2+ 12,39–41 . The cation-nucleotide complex (e.g.…”