Serine racemase: An unconventional enzyme for an unconventional transmitter

The discovery of large amounts of D-serine in the brain challenged the dogma that only L-amino acids are relevant for eukaryotes. The levels of D-serine in the brain are higher than many L-amino acids and account for as much as one-third of L-serine levels. Several studies in the last decades have demonstrated a role of D-serine as an endogenous agonist of N-methyl-D-aspartate receptors (NMDARs). D-Serine is required for NMDAR activity during normal neurotransmission as well as NMDAR overactivation that takes place in neurodegenerative conditions. Still, there are many unanswered questions about D-serine neurobiology, including regulation of its synthesis, release and metabolism. Here, we review the mechanisms of D-serine synthesis by serine racemase and discuss the lessons we can learn from serine racemase knockout mice, focusing on the roles attributed to D-serine and its cellular origin.