| Serine racemase is a pyridoxal 5′‑phosphate–dependent dimeric enzyme in the fold‑type II family that catalyzes the reversible racemization of L‑serine to D‑serine and also performs β‑elimination to generate pyruvate and ammonia, making it the principal biosynthetic source of D‑serine in the mammalian brain and a regulator of local serine flux between signaling and metabolic pools. The enzyme contains a PLP‑binding lysine in its active site and conserved catalytic residues that support both racemase and β‑lyase chemistry, arranged in a dynamic homodimer whose conformational flexibility underlies substrate binding, catalysis, and modulation by allosteric ligands such as divalent cations and Mg‑ATP. D‑serine produced by serine racemase serves as an essential co‑agonist at the glycine site of NMDA receptors, and the enzyme is enriched in forebrain regions where glutamatergic neurotransmission and long‑term potentiation are prominent; genetic and pharmacologic manipulation of serine racemase alters D‑serine levels, NMDA receptor activation, synaptic plasticity, and neuronal migration, positioning this enzyme as a key upstream control point in glutamate‑dependent signaling networks. Regulation of serine racemase activity integrates multiple inputs: ATP and divalent cations stimulate racemase function, while post‑translational mechanisms such as S‑nitrosylation, phosphorylation, and protein–protein interactions at the N‑ and C‑termini tune activity and stability, and the competing β‑elimination reaction provides a mechanism to drain L‑serine away from D‑serine production under conditions where dampening NMDA co‑agonist tone is advantageous. Expression and activity of serine racemase and D‑serine levels change across aging and neurodegenerative disease: hippocampal SR and D‑serine decline with normal aging in association with impaired cognition, whereas SR is upregulated in Alzheimer’s disease brain and elevated D‑serine has been reported in brain, CSF, or serum in subsets of AD patients, consistent with a shift from NMDA hypofunction in aging to hyperactivation and excitotoxicity in dementia. Abnormal SR–D‑serine–NMDA coupling in ischemic stroke, ALS, schizophrenia, and other neuropsychiatric disorders, with both excessive and deficient D‑serine linked to pathology, and the detailed characterization of SR’s catalytic mechanism and conformational energy landscape has spurred efforts to develop selective inhibitors and modulators as potential therapeutics to normalize NMDA receptor co‑agonist tone. |
