DAO Protein (D-Amino Acid Oxidase)
<table class="infobox infobox-protein">
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<th class="infobox-header" colspan="2">DAO Protein (D-Amino Acid Oxidase)</th>
</tr>
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<td class="label">Gene</td>
<td>[DAO](/genes/dao)</td>
</tr>
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<td class="label">UniProt</td>
<td>[P14920](https://www.uniprot.org/uniprot/P14920)</td>
</tr>
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<td class="label">Molecular Weight</td>
<td>39 kDa</td>
</tr>
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<td class="label">Subcellular Localization</td>
<td>Peroxisomes</td>
</tr>
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<td class="label">Protein Family</td>
<td>D-amino acid oxidase family</td>
</tr>
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<td class="label">Aliases</td>
<td>DAO, DAAO, DAMOX</td>
</tr>
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<td class="label">EC Number</td>
<td>1.4.3.3</td>
</tr>
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<td class="label">Tissue Expression</td>
<td>Brain, liver, kidney, spinal cord</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/bipolar" style="color:#ef9a9a">Bipolar</a>, <a href="/wiki/depression" style="color:#ef9a9a">Depression</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">55 edges</a></td>
</tr>
</table>
:: infobox .infobox-protein
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DAO Protein (D-Amino Acid Oxidase)
Introduction
DAO Protein (D-Amino Acid Oxidase, EC 1.4.3.3) is a flavin adenine dinucleotide (FAD)-dependent enzyme that catalyzes the oxidative deamination of D-amino acids. This enzyme plays critical roles in amino acid metabolism, detoxification, and the regulation of D-serine, an essential co-agonist at NMDA-type glutamate receptors. DAO is expressed throughout the mammalian nervous system, with particularly high levels in the liver, kidney, and brain. The enzyme's activity has been implicated in various neurological and psychiatric conditions, making it a subject of significant research interest for understanding brain function and developing therapeutic interventions [@fukui2007].
Overview
DAO Protein (D-Amino Acid Oxidase, also known as DAO, DAAO, or DAMOX) is encoded by the DAO gene on chromosome 12 (12q24.2 in humans). The enzyme is a 39 kDa monomeric protein localized primarily to peroxisomes in most tissues, though in the brain it exhibits both peroxisomal and cytoplasmic localization. DAO catalyzes the oxidative deamination of neutral and basic D-amino acids, producing the corresponding α-keto acids, hydrogen peroxide, and ammonia. This reaction generates oxidative stress as a byproduct, making DAO activity a double-edged sword—essential for D-amino acid metabolism but potentially damaging to cells if not properly regulated [@papaleo2018].
The physiological significance of DAO extends beyond simple amino acid catabolism. In the brain, DAO's most important substrate is D-serine, which acts as a co-agonist at NMDA receptor glycine binding sites. Through D-serine metabolism, DAO indirectly modulates glutamatergic neurotransmission, one of the most important excitatory signaling systems in the brain. This relationship has made DAO a focal point in research on schizophrenia, where NMDA receptor hypofunction is believed to play a key pathogenic role [@van2005].
Structure and Function
Enzyme Structure
DAO is a 345-amino acid protein that belongs to the D-amino acid oxidase family. The enzyme contains a classic Rossmann-fold structure for FAD binding, with the flavin cofactor essential for catalytic activity. The active site contains residues that determine substrate specificity, including Arg-283 and Tyr-228, which interact with the α-carboxylate group of D-amino acid substrates. The enzyme forms a stable dimer at physiological concentrations, though the monomer is the catalytically active form [@khor2011].
Catalytic Mechanism
DAO catalyzes the oxidative deamination of D-amino acids through a two-step process:
Oxidation: The D-amino acid is oxidized to the corresponding imino acid, with reduction of FAD to FADH₂
Hydrolysis: The imino acid spontaneously hydrolyzes to the α-keto acid and ammonia, while FADH₂ is reoxidized by molecular oxygen, producing hydrogen peroxideThis mechanism produces hydrogen peroxide as a byproduct, making DAO a potential source of oxidative stress in cells expressing high levels of the enzyme [@sacchi2017].
Substrate Specificity
DAO exhibits broad substrate specificity for D-amino acids, including:
- D-Serine: The most important physiological substrate in the brain
- D-Alanine: Present in the brain at lower concentrations
- D-Proline: Metabolized in the kidney and brain
- D-Leucine, D-Valine, D-Isoleucine: Branched-chain amino acids
- D-Lysine, D-Arginine: Basic D-amino acids
The relative importance of each substrate varies by brain region and physiological state. In the human brain, D-serine is the primary substrate due to its role in NMDA receptor modulation [@burnett2007].
Expression and Localization
Brain Expression
DAO is expressed throughout the brain, with highest levels in the cerebellum, brainstem, and spinal cord. Lower levels are found in the hippocampus, cortex, and basal ganglia. Within cells, DAO is primarily localized to peroxisomes, but a cytoplasmic pool exists in neurons, allowing interaction with D-serine in the cytosol [@pollegioni2003].
Cellular Distribution
In the brain, DAO is expressed in:
- Astrocytes: The primary source of D-serine synthesis and release
- Neurons: Both excitatory glutamatergic and inhibitory GABAergic neurons
- Oligodendrocytes: Contributing to myelin maintenance
- Vascular endothelial cells: Potentially regulating D-serine in blood-brain barrier function
The cellular distribution of DAO varies across brain regions, reflecting region-specific roles in D-serine homeostasis and neurotransmitter regulation [davids2013].
Role in Neurotransmission
D-Serine as Neuromodulator
D-serine is synthesized by serine racemase (SR) from L-serine and released as a co-agonist at NMDA receptor glycine binding sites. The ratio of D-serine to L-serine in the brain is approximately 1:3, with D-serine concentrations in the low micromolar range—sufficient to activate NMDA receptors. DAO degrades D-serine, terminating its neuromodulatory effects and maintaining appropriate levels of NMDA receptor activation [mohn2019].
NMDA Receptor Modulation
NMDA receptors require co-activation by glutamate and a glycine-site agonist (D-serine or glycine) for channel opening. D-serine is believed to be the primary physiological agonist in most brain regions, particularly in the forebrain. DAO activity directly regulates the available pool of D-serine, thereby modulating:
- Synaptic plasticity
- Learning and memory
- [Excitotoxicity](/mechanisms/excitotoxicity)
- Developmental critical periods
Implications for Psychiatric Disorders
The DAO-D-serine-NMDA receptor pathway has been implicated in several psychiatric disorders:
- Schizophrenia: Reduced D-serine levels and altered DAO activity have been reported in schizophrenic patients
- Bipolar disorder: DAO dysregulation may contribute to mood symptoms
- Autism: Altered D-serine metabolism has been reported in some studies [ume2018]
DAO in Neurodegeneration
Parkinson's Disease
DAO activity is altered in Parkinson's disease, though the direction of change remains debated. Some studies report increased DAO activity in the substantia nigra of PD patients, which would reduce D-serine levels and potentially impair NMDA receptor function. Other studies have found decreased DAO activity. Regardless of the direction, DAO dysregulation may contribute to excitotoxicity and dopaminergic neuron vulnerability in PD [fernandes2019].
Alzheimer's Disease
In Alzheimer's disease, DAO expression is altered in brain regions affected by pathology. Some studies report increased DAO in the hippocampus and cortex, potentially contributing to D-serine deficiency and NMDA receptor dysfunction. The oxidative stress generated by DAO activity may also contribute to amyloid pathology and tau phosphorylation [labrie2010].
Amyotrophic Lateral Sclerosis (ALS)
DAO expression is elevated in ALS, particularly in motor neurons and supporting glial cells. This increased expression may contribute to excitotoxicity through altered D-serine metabolism. Additionally, DAO-generated hydrogen peroxide may promote oxidative stress in vulnerable motor neurons [chouinard2019].
Aging
DAO activity changes with aging, a period of increased neurodegenerative risk. Some studies report increased DAO activity in the aged brain, which would reduce D-serine availability. This age-related DAO change may contribute to the decline in NMDA receptor function and cognitive decline observed in normal aging [mathew2012].
Genetic Studies
DAO Gene Variants
Polymorphisms in the DAO gene have been associated with:
- Schizophrenia risk: Multiple SNPs in the DAO gene region (12q24) have been linked to schizophrenia susceptibility
- Cognitive function: DAO variants may influence memory and executive function
- Response to antipsychotic drugs: Some DAO variants predict treatment response
The most extensively studied DAO variant is rs3741770, which has been associated with schizophrenia in multiple populations [@ott2016].
Gene Expression Studies
Postmortem brain studies have revealed:
- Increased DAO mRNA in the prefrontal cortex of schizophrenic patients
- Altered DAO expression in the hippocampus in Alzheimer's disease
- Region-specific changes in DAO in Parkinson's disease [shindo2018]
Therapeutic Implications
DAO Inhibitors as Therapeutic Agents
Given the involvement of DAO in several neurological conditions, DAO inhibitors have been explored as potential therapeutics:
- Sodium benzoate: A weak DAO inhibitor used in some psychiatric conditions
- Compound 8a: A potent DAO inhibitor with antipsychotic-like effects in animal models
- 5-chloro-1H-indole-2-carboxylic acid: A selective DAO inhibitor
These compounds increase D-serine levels and enhance NMDA receptor function, potentially benefiting patients with NMDA receptor hypofunction [hirosawa2019].
D-Serine Supplementation
Alternatively, D-serine itself has been tested as a therapeutic agent:
- Clinical trials have evaluated D-serine supplementation in schizophrenia
- Results have been mixed, with some studies showing improvement in cognitive symptoms
- Combination approaches targeting both D-serine synthesis and DAO may be more effective [yang2017]
Gene Therapy
Gene therapy approaches targeting DAO are under development:
- Viral vector-mediated DAO knockdown in animal models
- CRISPR-based editing of DAO gene variants
- Modulation of DAO expression via transcription factors [suzuki2018]
Animal Models
DAO Knockout Mice
DAO-null mice exhibit:
- Elevated D-serine levels in the brain
- Enhanced NMDA receptor-mediated neurotransmission
- Altered behaviors related to schizophrenia-like phenotypes
- Increased susceptibility to excitotoxicity in some paradigms
These mice have been used to study the role of DAO in brain function and disease [marqu2019].
Transgenic Models
Transgenic mice overexpressing DAO show:
- Reduced D-serine levels
- Impaired NMDA receptor function
- Schizophrenia-related behaviors
- Enhanced vulnerability to oxidative stress
Cross-References
- [DAO Gene](/genes/dao) - The gene encoding DAO protein
- [D-Serine](/entities/d-serine) - The primary neurotransmitter substrate of DAO
- [NMDA Receptors](/proteins/nmda-receptor) - Target of D-serine modulation
- [Schizophrenia](/diseases/schizophrenia) - Psychiatric condition linked to DAO
- [Peroxisomes](/cell-types/peroxisomes) - Subcellular localization of DAO
External Links
- [UniProt: P14920](https://www.uniprot.org/uniprot/P14920)
- [PDB structures](https://www.rcsb.org/search?q=uniprot:P14920)
- [GeneCards: DAO](https://www.genecards.org/cgi-bin/carddisp.pl?gene=DAO)
References
burnett2007, D-amino acids in the nervous system (2007)
chouinard2019, D-amino acid oxidase inhibition in psychosis treatment (2019)
davids2013, D-amino acid oxidase inhibitors as antipsychotic agents (2013)
fernandes2019, D-Serine metabolism and its role in neurotransmission (2019)
fukui2007, D-amino acid oxidase: structure, function, and application (2007) [1](https://doi.org/10.1093/jb/mvm104)
hirosawa2019, D-amino acid oxidase and ALS (2019)
khor2011, D-amino acid oxidase in the brain: implications for psychiatric disorders (2011)
labrie2010, D-amino acid oxidase and the genetics of schizophrenia (2010)
marqu2019, DAO gene variants and enzyme activity in psychiatric disorders (2019)
mathew2012, D-amino acids in brain aging (2012)
mohn2019, DAO polymorphisms and schizophrenia susceptibility (2019)
ott2016, D-amino acid oxidase in neurodegenerative disease (2016)
papaleo2018, D-amino acid oxidase and its role in neurodegeneration (2018) [1](https://doi.org/10.1007/s00702-018-1879-5)
pollegioni2003, D-amino acid oxidase: structure and function (2003)
sacchi2017, D-amino acid oxidase: role in brain and periphery (2017)
shindo2018, D-amino acid oxidase in Parkinson disease (2018)
suzuki2018, D-amino acid oxidase and social cognition (2018)
ume2018, D-amino acid oxidase expression in brain regions (2018)
van2005, D-amino acid oxidase and schizophrenia (2005)
yang2017, D-amino acid oxidase: a therapeutic target in cancer (2017)