Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligand for the glycinemodulatory
binding site on the NR1 subunit of N-methyl-D-aspartate receptors in various brain areas. Cellular concentrations of D-serine
are regulated by synthesis due to the enzyme serine racemase (isomerization reaction) and by degradation due to the same enzyme
(elimination reaction) as well as by the FAD-containing flavoenzyme D-amino acid oxidase (DAAO, oxidative deamination reaction).
Several findings have linked low levels of D-serine to schizophrenia: D-serine concentrations in serum and cerebrospinal fluid have been
reported to be decreased in schizophrenia patients while human DAAO activity and expression are increased; oral administration of Dserine
improved positive, negative, and cognitive symptoms of schizophrenia as add-on therapy to typical and atypical antipsychotics.
This evidence indicates that increasing NMDA receptor function, perhaps by inhibiting DAAO-induced degradation of D-serine may alleviate
symptoms in schizophrenic patients. Furthermore, it has been suggested that co-administration of D-serine with a human DAAO
inhibitor may be a more effective means of increasing D-serine levels in the brain. Here, we present an overview of the current knowledge
of the structure-function relationships in human DAAO and of the compounds recently developed to inhibit its activity (specifically
the ones recently exploited for schizophrenia treatment).
Keywords: Schizophrenia, D-serine, NMDA receptor, inhibitors
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