DAO

Official Full Name

D-amino acid oxidase

Organism

Homo sapiens

GeneID

1610

Background

This gene encodes the peroxisomal enzyme D-amino acid oxidase. The enzyme is a flavoprotein which uses flavin adenine dinucleotide (FAD) as its prosthetic group. Its substrates include a wide variety of D-amino acids, but it is inactive on the naturally occurring L-amino acids. Its biological function is not known; it may act as a detoxifying agent which removes D-amino acids that accumulate during aging. In mice, it degrades D-serine, a co-agonist of the NMDA receptor. This gene may play a role in the pathophysiology of schizophrenia. [provided by RefSeq, Jul 2008]

Synonyms

DAAO; OXDA; DAMOX;

Bio Chemical Class

CH-NH donor oxidoreductase

Protein Sequence

MRVVVIGAGVIGLSTALCIHERYHSVLQPLDIKVYADRFTPLTTTDVAAGLWQPYLSDPNNPQEADWSQQTFDYLLSHVHSPNAENLGLFLISGYNLFHEAIPDPSWKDTVLGFRKLTPRELDMFPDYGYGWFHTSLILEGKNYLQWLTERLTERGVKFFQRKVESFEEVAREGADVIVNCTGVWAGALQRDPLLQPGRGQIMKVDAPWMKHFILTHDPERGIYNSPYIIPGTQTVTLGGIFQLGNWSELNNIQDHNTIWEGCCRLEPTLKNARIIGERTGFRPVRPQIRLEREQLRTGPSNTEVIHNYGHGGYGLTIHWGCALEAAKLFGRILEEKKLSRMPPSHL

Open

Disease

Ataxic disorder, Mild neurocognitive disorder, Schizophrenia

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

1 +

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Detailed Information

The DAO gene is a crucial gene encoding D-amino acid oxidase (DAAO), a flavin adenine dinucleotide (FAD)-dependent peroxidase. This enzyme can selectively oxidize various neutral D-amino acids, converting them into imino acids, hydrogen peroxide, and ammonia. The imino acids spontaneously hydrolyze into α-keto acids. This characteristic enables DAO to play an indispensable role in metabolic regulation within the body. Despite its inactivity toward L-amino acids, DAO's efficient catalytic activity on D-amino acids is considered vital for maintaining the balance of D-amino acids and clearing potential metabolic toxins. DAO is widely distributed in organs like the liver, kidneys, and brain in mammals, with its expression variability in different tissues directly determining its diverse and complex functions.

DAO is important in the brain because it helps control the levels of D-serine, which affects how NMDA receptors work. NMDA receptors are a type of ionotropic glutamate receptor that play a key role in important brain functions like learning, memory, and changes in synapses. Because of this, the work of DAO in breaking down D-serine is important for controlling how neurotransmitters function. DAO is also found in the defense system and may help neutrophils by producing hydrogen peroxide, which can effectively kill germs and prevent their growth.

Role of DAO in the Nervous System and Its Association with Mental Disorders

The primary function of DAO in the nervous system is its regulation of D-serine metabolism. D-serine helps activate NMDA receptors by working together with glutamate. Both must bind to the receptors to send signals to the brain. This process is important for keeping neurons working properly, helping to strengthen connections between them, and allowing us to learn and remember things. Too much or too little D-serine in the body can negatively impact how NMDA receptors work.

Figure 1 illustrates synaptic regulation and the catabolism of D-serine by D-amino acid oxidase (DAO), showing both a traditional and expanded view of D-serine synthesis, release, action, and degradation in the central nervous system. Figure 1. Synaptic regulation and D-amino acid oxidase (DAO) catabolism of D-serine. (Verrall L, et al., 2010)

Research indicates that abnormal DAO activity is closely related to various mental disorders. Elevated DAO expression or activity is often observed in the brains of individuals with schizophrenia, potentially leading to reduced D-serine concentrations and weakened NMDA receptor function, manifesting in core symptoms such as learning difficulties and cognitive decline. Certain single nucleotide polymorphisms (SNPs) in the DAO gene have been significantly associated with schizophrenia risk, suggesting that DAO might be an important target in this disease. Moreover, DAO activity may also be linked to mood disorders like anxiety and depression, although the specific molecular mechanisms remain unclear.

Metabolic Characteristics of DAO and Its Functions in Other Physiological Systems

DAO's catalytic reaction is not limited to D-serine metabolism; it also degrades other D-amino acids such as D-alanine, D-valine, and D-tryptophan. Hydrogen peroxide generated by DAO exhibits different biological effects in various tissue environments. For instance, in the kidneys, hydrogen peroxide accumulation may exacerbate the pathological progression of chronic kidney disease through oxidative stress induction; in the intestines, hydrogen peroxide secreted by DAO can inhibit pathogen growth, thereby maintaining intestinal microbiota homeostasis.

DAO's function in the intestines is particularly noteworthy. Intestinal epithelial cells secrete DAO to directly regulate D-amino acid metabolism in the lumen, clearing harmful D-amino acids produced by gut microbes. This process not only helps maintain microbiome balance but also reduces pathogen colonization risk, thereby protecting the host from infections. Additionally, DAO activity is regulated by diet, with high-protein diets generally inducing significant DAO expression upregulation, while vegetarian or low-protein diets may inhibit its activity, reflecting DAO's adaptive role in metabolic regulation.

Role of DAO in Pathophysiology

DAO's function may undergo significant changes under certain pathological conditions. For instance, abnormal DAO activity is thought to play a major role in chronic pain regulation. Studies have shown that decreased DAO activity in chronic pain models leads to D-serine accumulation, excessively activating NMDA receptors in the spinal cord and causing hyperalgesia. In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), DAO dysfunction may influence disease progression through multiple mechanisms. Specific mutations in the DAO gene, such as the R199W mutation, weaken the enzyme's catalytic activity and lead to the formation of toxic protein aggregates in neurons, a process closely related to ALS pathology.

DAO also plays a significant role in systemic diseases like metabolic syndrome and diabetes. Abnormal DAO activity may lead to disrupted D-amino acid metabolism, exacerbating insulin resistance or inflammatory responses through oxidative stress pathways. For instance, hydrogen peroxide produced by DAO may act as a signaling molecule at low doses but induce tissue damage at high concentrations, indicating a complex regulatory function of DAO in maintaining metabolic homeostasis.

References:

Pollegioni L, Sacchi S, et al. Human D-Amino Acid Oxidase: Structure, Function, and Regulation. Front Mol Biosci. 2018 Nov 28;5:107.
Sacchi S, Rosini E, et al. D-amino acid oxidase inhibitors as a novel class of drugs for schizophrenia therapy. Curr Pharm Des. 2013;19(14):2499-511.
Verrall L, Burnet PW, et al. The neurobiology of D-amino acid oxidase and its involvement in schizophrenia. Mol Psychiatry. 2010;15(2):122-137.

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