D-amino acid oxidase (DAAO) (DAAO)

D-amino acid oxidase (DAAO) is a peroxisomal flavoenzyme that catalyzes the oxidative deamination of neutral and polar D-amino acids, such as D-serine and D-alanine, into their corresponding alpha-keto acids, ammonia, and hydrogen peroxide (UniProt [3], [17]). In the central nervous system, DAAO is the primary enzyme responsible for the degradation of D-serine, a critical endogenous co-agonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor (PubMed [1], [13]). Increased expression and activity of DAAO have been observed in the brains of patients with schizophrenia, leading to reduced D-serine levels and subsequent NMDA receptor hypofunction, which is linked to cognitive and negative symptoms (PMC [2], [15]). Consequently, DAAO is a major therapeutic target for the development of inhibitors aimed at restoring NMDA receptor signaling by increasing synaptic D-serine concentrations (PubMed [9], [12]). Beyond its role in psychiatric disorders, DAAO is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) through specific mutations and plays a detoxifying role in the liver and kidneys (NCBI [16], [11]). Clinical candidates like luvadaxistat (TAK-831) have been evaluated in trials for their potential to treat cognitive impairment associated with schizophrenia (PMC [5], [12]).

Other names

DAOOXDADAMOXD-amino-acid oxidase

DAAO inhibitors block the oxidative deamination of D-serine, thereby increasing its availability as a co-agonist for the NMDA receptor. This enhancement of NMDA receptor-mediated neurotransmission is intended to alleviate cognitive and negative symptoms in schizophrenia and other disorders associated with glutamatergic hypofunction (PubMed [1], [12]).