D-amino acid oxidase

D-amino acid oxidase (DAO) is an enzyme that is encoded by the DAO gene in humans. This enzyme catalyzes the oxidative deamination of D-amino acids to their corresponding imino acids, which are subsequently hydrolyzed to produce the corresponding keto acids and ammonia. The enzyme is a peroxisomal flavoprotein, containing FAD as a cofactor, and is involved in the catabolism of D-amino acids present in the diet, as well as in the central nervous system and peripheral tissues. D-amino acid oxidase plays a crucial role in the metabolism of D-serine, a co-agonist of the NMDA receptor, suggesting its importance in the modulation of glutamatergic neurotransmission in the brain.

Function

D-amino acid oxidase is responsible for the degradation of D-amino acids by catalyzing their oxidation. This process involves the removal of an amino group, forming the corresponding keto acid and producing hydrogen peroxide as a byproduct. The enzyme's activity is particularly significant in the metabolism of D-serine, a neurotransmitter involved in the functioning of the NMDA receptor, which is critical for synaptic plasticity, learning, and memory. By regulating the levels of D-serine, DAO indirectly influences NMDA receptor activity and thus plays a role in neurophysiological processes and potentially in neurological disorders.

Clinical Significance

Alterations in the activity or expression of D-amino acid oxidase have been implicated in several neurological and psychiatric disorders, including schizophrenia, bipolar disorder, and amyotrophic lateral sclerosis (ALS). Elevated levels of DAO activity may lead to a decrease in D-serine levels, affecting NMDA receptor function and contributing to the pathophysiology of these conditions. Consequently, inhibitors of DAO are being explored as potential therapeutic agents for diseases associated with NMDA receptor hypofunction.

Genetics

The DAO gene is located on chromosome 12q24 and consists of multiple exons that span a considerable length of genomic DNA. Variants within the DAO gene or its regulatory regions have been studied in the context of their potential association with psychiatric and neurological disorders, although results have been mixed and further research is needed to clarify these relationships.

Inhibitors

Several compounds have been identified as inhibitors of D-amino acid oxidase, including benzoate and certain derivatives of D-amino acids. These inhibitors have the potential to increase the levels of D-serine in the brain, thereby enhancing NMDA receptor-mediated neurotransmission. This mechanism has been proposed as a novel therapeutic approach for the treatment of disorders associated with NMDA receptor dysfunction.

See Also

• Amino acid metabolism
• NMDA receptor
• Schizophrenia
• Bipolar disorder
• Amyotrophic lateral sclerosis

References

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  Crystal structure of RgDAAO

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  HDAAO Head-to-Head Connection

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  D-amino acid oxidase