title: D-amino acid oxidase inhibitors as a novel class of drugs for schizophrenia therapy.
abstract: Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligand for the glycine modulatory 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 D-serine 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).
authors.affiliation: Dipartimento di Biotecnologie e Scienze della Vita, via J.H. Dunant 3, 21100 Varese, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sacchi
authors.forename: Elena
authors.initials: E
authors.lastname: Rosini
authors.forename: Loredano
authors.initials: L
authors.lastname: Pollegioni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Molla
mesh_terms: D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000201:enzymology; D012694:Serine / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D003605:D-Amino-Acid Oxidase