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gene_id: DDO
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protein_description: 'RecName: Full=D-aspartate oxidase; Short=DASOX {ECO:0000305};
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gene_info: Name=DDO {ECO:0000305}; Synonyms=LOC115226122;
organism_full: Octopus vulgaris (Common octopus).
protein_family: Belongs to the DAMOX/DASOX family. .
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

• UniProt Accession: A0A7E6FSU6
• Protein Description: RecName: Full=D-aspartate oxidase; Short=DASOX {ECO:0000305}; Short=DASPO {ECO:0000250|UniProtKB:Q99489}; Short=DDO {ECO:0000305}; EC=1.4.3.1 {ECO:0000269|PubMed:7915543};
• Gene Information: Name=DDO {ECO:0000305}; Synonyms=LOC115226122;
• Organism (full): Octopus vulgaris (Common octopus).
• Protein Family: Belongs to the DAMOX/DASOX family. .
• Key Domains: D-amino_acid_oxidase_CS. (IPR006181); DAO. (IPR023209); FAD-dep_OxRdtase. (IPR006076); DAO (PF01266)

MANDATORY VERIFICATION STEPS:

1. Check if the gene symbol "DDO" matches the protein description above
2. Verify the organism is correct: Octopus vulgaris (Common octopus).
3. Check if protein family/domains align with what you find in literature
4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'DDO' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene DDO (gene ID: DDO, UniProt: A0A7E6FSU6) in OCTVU.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

• UniProt Accession: A0A7E6FSU6
• Protein Description: RecName: Full=D-aspartate oxidase; Short=DASOX {ECO:0000305}; Short=DASPO {ECO:0000250|UniProtKB:Q99489}; Short=DDO {ECO:0000305}; EC=1.4.3.1 {ECO:0000269|PubMed:7915543};
• Gene Information: Name=DDO {ECO:0000305}; Synonyms=LOC115226122;
• Organism (full): Octopus vulgaris (Common octopus).
• Protein Family: Belongs to the DAMOX/DASOX family. .
• Key Domains: D-amino_acid_oxidase_CS. (IPR006181); DAO. (IPR023209); FAD-dep_OxRdtase. (IPR006076); DAO (PF01266)

MANDATORY VERIFICATION STEPS:

1. Check if the gene symbol "DDO" matches the protein description above
2. Verify the organism is correct: Octopus vulgaris (Common octopus).
3. Check if protein family/domains align with what you find in literature
4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'DDO' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene DDO (gene ID: DDO, UniProt: A0A7E6FSU6) in OCTVU.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Functional Annotation of DDO / D-aspartate oxidase in Octopus vulgaris (UniProt A0A7E6FSU6)

0. Target verification (critical identity check)

The UniProt entry A0A7E6FSU6 is annotated as D-aspartate oxidase (synonyms: DASOX/DASPO/DDO; EC 1.4.3.1) from Octopus vulgaris, belonging to the DAO-like (DAMOX/DASOX) FAD-dependent oxidoreductase family. Primary biochemical literature in O. vulgaris directly characterizes a D-aspartate oxidase (EC 1.4.3.1) purified from O. vulgaris hepatopancreas and documents its flavin dependence and catalytic behavior, matching the UniProt identity and avoiding symbol ambiguity (tedeschi1994propertiesofthe pages 1-2, d’aniello2005cephalopodvisioninvolves pages 2-3).

1. Key concepts and definitions (current understanding)

1.1 Enzyme definition and core reaction

D-aspartate oxidase (DDO; also called DASPO) is an FAD-dependent oxidase that catalyzes oxidative deamination of acidic D-amino acids. In mammalian systems, the canonical reaction is described as oxidation of D-aspartate to oxaloacetate, with production of NH3 and H2O2 through reoxidation of reduced FAD by molecular oxygen (molla2020structureandkinetic pages 1-5, puggioni2020biochemicalcharacterizationof pages 1-2, usiello2020newevidenceon pages 1-3). Mechanistically, human DASPO is described as operating by a ternary-complex mechanism (oxygen reacts with the reduced flavin–imino acid complex before product release) with hydride transfer from the substrate α-carbon to flavin N5 (pollegioni2021humandaspartateoxidase pages 4-5).

Cephalopod-specific confirmation: In O. vulgaris, D-aspartate oxidase has been purified and characterized as a flavoprotein enzyme consistent with this oxidase class (tedeschi1994propertiesofthe pages 1-2).

1.2 Substrate specificity

Across taxa, DDO/DASPO is distinguished from D-amino acid oxidase (DAAO) by preference for acidic D-amino acids. Human DASPO is described as selective for acidic D-amino acids (e.g., D-Asp) that are not substrates for DAAO (pollegioni2021humandaspartateoxidase pages 2-4).

Cephalopods: The O. vulgaris D-aspartate oxidase oxidizes D-Asp and D-Glu, and to a lesser extent NMDA (N-methyl-D-aspartate) (d’aniello2005cephalopodvisioninvolves pages 2-3). A marine invertebrate enzyme survey reports that, for octopus liver DDO, substrate preference included Asp > D-glutamate > NMDA > D-asparagine (sarower2004distributionandsubstrate pages 4-5). In squid liver DDO (used as comparative cephalopod evidence), best substrates were reported as meso-2,3-diaminosuccinate and acidic derivatives (sarower2004distributionandsubstrate pages 3-4, sarower2004distributionandsubstrate pages 1-2).

1.3 Cofactor usage, enzyme state, and structural class

FAD dependence is a defining feature. In O. vulgaris, purified DDO is a monomer (~37 kDa) containing 1 mol flavin per mol protein, and was found in at least two cofactor forms: an active FAD form and a catalytically inactive form likely containing 6-OH-FAD, based on absorption spectra (tedeschi1994propertiesofthe pages 1-2).

For human DASPO, full-length enzyme binds one noncovalent FAD per ~39–40 kDa monomer and displays tight FAD binding (Kd in the tens of nM range), supporting the concept that holoenzyme predominates in vivo (molla2020structureandkinetic pages 11-13, pollegioni2021humandaspartateoxidase pages 4-5).

1.4 Cellular/subcellular localization (what is known vs inferred)

In mammals, DDO/DASPO is repeatedly described as a peroxisomal enzyme (pollegioni2021humandaspartateoxidase pages 2-4, usiello2020newevidenceon pages 1-3). Reviews further describe D-Asp and DDO as localized in neurons within peroxisomes, emphasizing compartmentalization and H2O2 handling (pollegioni2021humandaspartateoxidase pages 1-2).

For Octopus vulgaris specifically, the retrieved primary cephalopod papers characterize the enzyme biochemically but do not directly demonstrate subcellular localization. Therefore, peroxisomal localization for O. vulgaris DDO should be treated as high-confidence inference by orthology/family function, rather than a directly demonstrated localization in octopus tissues in the retrieved corpus.

2. Functional annotation of O. vulgaris DDO (A0A7E6FSU6)

2.1 Primary molecular function (enzyme activity)

Best-supported function: O. vulgaris DDO is an FAD-dependent oxidase catalyzing oxidative deamination of D-aspartate-class substrates (notably D-Asp, D-Glu; partial activity on NMDA) (d’aniello2005cephalopodvisioninvolves pages 2-3, tedeschi1994propertiesofthe pages 1-2).

The 1994 biochemical characterization reports features consistent with a DAO-like oxidase family enzyme, including flavin stoichiometry and catalytic group ionizations (two functional groups with apparent pKa ~7.1 and ~9.1 affecting catalysis differently for mono- vs dicarboxylic D-amino acids) (tedeschi1994propertiesofthe pages 1-2). This supports that the octopus enzyme is not only present but mechanistically specialized for acidic D-amino acid oxidation.

2.2 Tissue context in cephalopods (direct evidence)

Digestive gland/hepatopancreas (high-confidence): Cephalopod DDO activity is substantial in hepatopancreas/liver tissues (octopus; squid comparisons), supporting a role in metabolizing endogenous/exogenous acidic D-amino acids in these organs (sarower2004distributionandsubstrate pages 1-2, sarower2004distributionandsubstrate pages 3-4). O. vulgaris enzyme purification is reported from hepatopancreas (tedeschi1994propertiesofthe pages 1-2, d’aniello2005cephalopodvisioninvolves pages 2-3).

Visual system context (substrate pool evidence): High concentrations of free D-aspartate occur in cephalopod retina, including O. vulgaris (2.30 ± 0.25 µmol/g tissue), indicating a substantial physiological substrate pool for DDO-mediated catabolism in neural/visual tissues, though direct DDO localization/activity in retina is not explicitly quantified in the retrieved excerpts (d’aniello2005cephalopodvisioninvolves pages 7-8, d’aniello2005cephalopodvisioninvolves media d49ab66e).

Table: This table summarizes the strongest functional-annotation evidence for D-aspartate oxidase with emphasis on Octopus vulgaris and key conserved features from mammalian DASPO/DDO studies. It organizes what is directly demonstrated in cephalopods versus what is inferred from better-characterized orthologs.

3. Pathways and biological roles (with species-aware interpretation)

3.1 D-aspartate metabolism pathway

In mammals, DDO is described as the key catabolic control point for free D-Asp levels in brain and endocrine tissues, converting D-Asp to oxaloacetate and producing H2O2 as a byproduct (usiello2020newevidenceon pages 1-3). Postnatal onset of DDO expression is highlighted as a driver of the steep decline in brain D-Asp after birth (usiello2020newevidenceon pages 1-3, errico2015daspartateanendogenous pages 2-2).

In cephalopods, direct pathway modeling is limited in the retrieved corpus, but the combination of (i) substantial DDO activity in octopus digestive tissues and (ii) high D-Asp in optic/retinal tissues supports an annotation that O. vulgaris DDO participates in D-Asp clearance/homeostasis in tissues where D-Asp is present and potentially bioactive (sarower2004distributionandsubstrate pages 1-2, d’aniello2005cephalopodvisioninvolves pages 7-8).

3.2 Potential signaling relevance (cross-species inference)

D-Asp is described in mammalian literature as an endogenous agonist at NMDA receptors (binding the glutamate site), influencing glutamatergic signaling and synaptic plasticity; dysregulated D-Asp metabolism (including DDO expression/activity changes) is discussed in relation to neuropsychiatric phenotypes (pollegioni2021humandaspartateoxidase pages 1-2, errico2018theemergingrole pages 1-2). These mammalian roles motivate the hypothesis that DDO acts as a gatekeeper controlling D-Asp signaling capacity via catabolism.

Cephalopod-specific evidence relevant to the visual system: D-Asp is abundant in retina and optic lobes; radiotracer experiments indicate D-Asp can be produced in optic lobes and transported to the retina (d’aniello2005cephalopodvisioninvolves pages 7-8). While this does not directly assign a role to DDO, it establishes the substrate is dynamically handled in cephalopod visual circuitry.

4. Recent developments (prioritizing 2023–2024 sources)

4.1 2024: Peripheral biomarker evidence tied to the D-Asp/DDO axis (human)

A 2024 bicentric study measured fasting morning serum amino acids and reported reduced serum D-aspartate in schizophrenia compared with controls, with statistical evidence: F(2,35) = 8.397, p = 0.001, partial ηp² = 0.324; both non-treatment-resistant and treatment-resistant groups differed from controls (p = 0.0104 and p = 0.0177, respectively) (Garofalo et al., 2024; https://doi.org/10.3389/fpsyt.2024.1408175; published Jul 2024) (garofalo2024decreasedfreedaspartate pages 4-6).

Although this is not Octopus-specific, it represents a recent (2024) example of real-world clinical measurement of the D-Asp axis that is mechanistically linked in the schizophrenia literature to altered DDO expression/activity in brain (garofalo2024decreasedfreedaspartate pages 2-3).

4.2 2024: Updated expert synthesis—D-Asp signaling in reproduction with DDO genetic evidence

A 2024 review summarizes D-Asp signaling in testicular physiology and highlights that manipulating DDO (via Ddo knock-in models with lower testicular D-Asp) links DDO-regulated D-Asp availability to reduced steroidogenic readouts (including testosterone), placing DDO as a regulator of endocrine D-Asp signaling (Falvo et al., 2024; https://doi.org/10.3390/cells13161400; published Aug 2024) (falvo2024newinsightsinto pages 1-2, falvo2024newinsightsinto pages 2-3).

Again, not cephalopod-specific, but important for “current understanding” of how DDO controls D-Asp physiology beyond the nervous system.

5. Current applications and real-world implementations

5.1 Analytical/biochemical applications (directly relevant to cephalopod work)

Cephalopod studies use purified O. vulgaris D-aspartate oxidase as an analytical tool: treating tissue extracts with D-AspO abolishes the D-Asp peak in HPLC profiles, confirming analyte identity and enabling D-Asp quantification (d’aniello2005cephalopodvisioninvolves pages 4-5). More generally, DDO incubation is recommended as a control to confirm D-Asp peak identity in chromatographic assays (errico2015daspartateanendogenous pages 2-2).

5.2 Therapeutic strategy concept (expert opinion, supported by structure/chemistry)

Multiple authoritative sources argue that DDO inhibition could be used to raise endogenous D-Asp (thereby modulating NMDA-receptor-related physiology) as a potential therapeutic strategy for neuropsychiatric disorders (pollegioni2021humandaspartateoxidase pages 1-2, molla2020structureandkinetic pages 1-5). Structure/kinetic work positions DASPO structure as a platform for rational inhibitor discovery (molla2020structureandkinetic pages 1-5, molla2020structureandkinetic pages 16-18).

5.3 Inhibitor discovery and lead compounds (medicinal chemistry)

A medicinal chemistry study identified and characterized DDO inhibitors through in silico screening and in vitro functional assays, reporting 5-aminonicotinic acid inhibition of human DDO with Ki = 3.80 µM (Katane et al., 2015; https://doi.org/10.1021/acs.jmedchem.5b00871; published Sep 2015) (katane2015identificationofnovel pages 1-3). A human structural/kinetic study likewise reports 5-An as the best tested inhibitor with Ki ~3.8 µM and explicitly notes that “efficient inhibitors” remain to be identified, framing an unmet need for translation (molla2020structureandkinetic pages 1-5).

6. Quantitative data highlights (selected)

1. Retinal D-Asp concentrations (cephalopods): O. vulgaris retina contains 2.30 ± 0.25 µmol/g D-Asp (with higher values in Sepia officinalis), demonstrating a strong substrate pool in the visual system (D’Aniello et al., 2005; https://doi.org/10.1042/bj20041070; published Mar 2005) (d’aniello2005cephalopodvisioninvolves media d49ab66e).
2. Octopus DDO biochemical properties: monomer ~37 kDa, 1 flavin per enzyme, active FAD form and inactive 6-OH-FAD–like form (Tedeschi et al., 1994; https://doi.org/10.1016/0167-4838(94)00071-9; published Aug 1994) (tedeschi1994propertiesofthe pages 1-2).
3. Human DASPO kinetics/cofactor binding (cross-species inference): Km(D-Asp) ~1.05 mM, kcat ~81.3 s−1, FAD Kd ~33 nM, and tight FAD binding consistent with holoenzyme predominance (Pollegioni et al., 2021; https://doi.org/10.3389/fmolb.2021.689719; published Jun 2021) (pollegioni2021humandaspartateoxidase pages 4-5).
4. 2024 schizophrenia serum statistics: F(2,35)=8.397, p=0.001, ηp²=0.324 for serum D-Asp group differences (Garofalo et al., 2024; https://doi.org/10.3389/fpsyt.2024.1408175; published Jul 2024) (garofalo2024decreasedfreedaspartate pages 4-6).

7. Practical functional-annotation summary for O. vulgaris DDO (A0A7E6FSU6)

Molecular function: FAD-dependent oxidoreductase (EC 1.4.3.1) catalyzing oxidative deamination of acidic D-amino acids, especially D-aspartate and D-glutamate, producing the corresponding α-ketoacid (oxaloacetate for D-Asp), ammonia, and H2O2 (direct cephalopod activity: D-Asp/D-Glu oxidation; mammalian reaction equation used as conserved mechanism) (d’aniello2005cephalopodvisioninvolves pages 2-3, tedeschi1994propertiesofthe pages 1-2, molla2020structureandkinetic pages 1-5, usiello2020newevidenceon pages 1-3).

Substrate specificity: Cephalopod DDO has preference for D-Asp-class substrates; NMDA can be oxidized but typically with lower activity (d’aniello2005cephalopodvisioninvolves pages 2-3, sarower2004distributionandsubstrate pages 4-5).

Tissue context: Strongest direct evidence is digestive gland/hepatopancreas/liver (enzyme purification and activity surveys) (tedeschi1994propertiesofthe pages 1-2, sarower2004distributionandsubstrate pages 1-2). High D-Asp in retina/optic tissues suggests a potential (but not yet directly proven) role in neural/visual D-Asp homeostasis (d’aniello2005cephalopodvisioninvolves pages 7-8, d’aniello2005cephalopodvisioninvolves media d49ab66e).

Subcellular localization: Not experimentally localized in octopus in the retrieved sources; by strong orthology to mammalian DASPO, DDO is expected to be peroxisomal (mammalian direct evidence) (pollegioni2021humandaspartateoxidase pages 2-4, usiello2020newevidenceon pages 1-3).

8. Limitations and evidence gaps (important for correct annotation)

1. Octopus-specific subcellular localization (peroxisome vs other compartments) was not directly established in the retrieved cephalopod primary literature; any peroxisomal assignment is an inference based on well-characterized mammalian orthologs (pollegioni2021humandaspartateoxidase pages 2-4, usiello2020newevidenceon pages 1-3).
2. 2023–2024 octopus-specific DDO research was not identified in the retrieved corpus; the most direct cephalopod enzymology evidence remains from 1994–2005, with recent work primarily in mammals/humans.

Key references (URLs and publication dates)

• Tedeschi et al. “Properties of the flavoenzyme D-aspartate oxidase from Octopus vulgaris.” Biochim Biophys Acta (Aug 1994). https://doi.org/10.1016/0167-4838(94)00071-9 (tedeschi1994propertiesofthe pages 1-2)
• D’Aniello et al. “Cephalopod vision involves dicarboxylic amino acids: D-aspartate, L-aspartate and L-glutamate.” Biochem J (Mar 2005). https://doi.org/10.1042/bj20041070 (d’aniello2005cephalopodvisioninvolves pages 4-5, d’aniello2005cephalopodvisioninvolves media d49ab66e)
• Sarower et al. “Distribution and substrate specificity of D-amino acid and D-aspartate oxidases in marine invertebrates.” (2004; journal not captured in retrieved metadata) (sarower2004distributionandsubstrate pages 3-4, sarower2004distributionandsubstrate pages 1-2, sarower2004distributionandsubstrate pages 4-5)
• Pollegioni et al. “Human D-aspartate Oxidase: A Key Player in D-aspartate Metabolism.” Front Mol Biosci (Jun 2021). https://doi.org/10.3389/fmolb.2021.689719 (pollegioni2021humandaspartateoxidase pages 4-5, pollegioni2021humandaspartateoxidase pages 2-4)
• Garofalo et al. “Decreased free D-aspartate levels in the blood serum of patients with schizophrenia.” Front Psychiatry (Jul 2024). https://doi.org/10.3389/fpsyt.2024.1408175 (garofalo2024decreasedfreedaspartate pages 4-6, garofalo2024decreasedfreedaspartate pages 2-3)
• Falvo et al. “New Insights into D-Aspartate Signaling in Testicular Activity.” Cells (Aug 2024). https://doi.org/10.3390/cells13161400 (falvo2024newinsightsinto pages 1-2)
• Katane et al. “Identification of Novel D-Aspartate Oxidase Inhibitors…” J Med Chem (Sep 2015). https://doi.org/10.1021/acs.jmedchem.5b00871 (katane2015identificationofnovel pages 1-3)

References

1. (tedeschi1994propertiesofthe pages 1-2): Gabriella Tedeschi, Armando Negri, Fabrizio Ceciliani, Severino Ronchi, Amedeo Vetere, Gemma D'Aniello, and Antimo D'Aniello. Properties of the flavoenzyme d-aspartate oxidase from octopus vulgaris. Biochimica et biophysica acta, 1207 2:217-22, Aug 1994. URL: https://doi.org/10.1016/0167-4838(94)00071-9, doi:10.1016/0167-4838(94)00071-9. This article has 52 citations.

2. (d’aniello2005cephalopodvisioninvolves pages 2-3): S. D’Aniello, P. Spinelli, G. Ferrandino, K. Peterson, Mara Tsesarskia, G. Fisher, and A. D’Aniello. Cephalopod vision involves dicarboxylic amino acids: d-aspartate, l-aspartate and l-glutamate. The Biochemical journal, 386 Pt 2:331-40, Mar 2005. URL: https://doi.org/10.1042/bj20041070, doi:10.1042/bj20041070. This article has 52 citations.

3. (molla2020structureandkinetic pages 1-5): G Molla, A Chaves-Sanjuan, A Savinelli, and M Nardini. Structure and kinetic properties of human d-aspartate oxidase, the enzyme-controlling d-aspartate levels in brain. Unknown journal, 2020.

4. (puggioni2020biochemicalcharacterizationof pages 1-2): Vincenzo Puggioni, Antonio Savinelli, Matteo Miceli, Gianluca Molla, Loredano Pollegioni, and Silvia Sacchi. Biochemical characterization of mouse d-aspartate oxidase. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 1868:140472, Oct 2020. URL: https://doi.org/10.1016/j.bbapap.2020.140472, doi:10.1016/j.bbapap.2020.140472. This article has 9 citations and is from a peer-reviewed journal.

5. (usiello2020newevidenceon pages 1-3): Alessandro Usiello, Maria Maddalena Di Fiore, Arianna De Rosa, Sara Falvo, Francesco Errico, Alessandra Santillo, Tommaso Nuzzo, and Gabriella Chieffi Baccari. New evidence on the role of d-aspartate metabolism in regulating brain and endocrine system physiology: from preclinical observations to clinical applications. International Journal of Molecular Sciences, 21:8718, Nov 2020. URL: https://doi.org/10.3390/ijms21228718, doi:10.3390/ijms21228718. This article has 55 citations.

6. (pollegioni2021humandaspartateoxidase pages 4-5): Loredano Pollegioni, Gianluca Molla, Silvia Sacchi, and Giulia Murtas. Human d-aspartate oxidase: a key player in d-aspartate metabolism. Frontiers in Molecular Biosciences, Jun 2021. URL: https://doi.org/10.3389/fmolb.2021.689719, doi:10.3389/fmolb.2021.689719. This article has 31 citations.

7. (pollegioni2021humandaspartateoxidase pages 2-4): Loredano Pollegioni, Gianluca Molla, Silvia Sacchi, and Giulia Murtas. Human d-aspartate oxidase: a key player in d-aspartate metabolism. Frontiers in Molecular Biosciences, Jun 2021. URL: https://doi.org/10.3389/fmolb.2021.689719, doi:10.3389/fmolb.2021.689719. This article has 31 citations.

8. (sarower2004distributionandsubstrate pages 4-5): MG Sarower, T Matsui, and H Abe. Distribution and substrate specificity of d-amino acid and d-aspartate oxidases in marine invertebrates. Unknown journal, 2004.

9. (sarower2004distributionandsubstrate pages 3-4): MG Sarower, T Matsui, and H Abe. Distribution and substrate specificity of d-amino acid and d-aspartate oxidases in marine invertebrates. Unknown journal, 2004.

10. (sarower2004distributionandsubstrate pages 1-2): MG Sarower, T Matsui, and H Abe. Distribution and substrate specificity of d-amino acid and d-aspartate oxidases in marine invertebrates. Unknown journal, 2004.

11. (molla2020structureandkinetic pages 11-13): G Molla, A Chaves-Sanjuan, A Savinelli, and M Nardini. Structure and kinetic properties of human d-aspartate oxidase, the enzyme-controlling d-aspartate levels in brain. Unknown journal, 2020.

12. (pollegioni2021humandaspartateoxidase pages 1-2): Loredano Pollegioni, Gianluca Molla, Silvia Sacchi, and Giulia Murtas. Human d-aspartate oxidase: a key player in d-aspartate metabolism. Frontiers in Molecular Biosciences, Jun 2021. URL: https://doi.org/10.3389/fmolb.2021.689719, doi:10.3389/fmolb.2021.689719. This article has 31 citations.

13. (d’aniello2005cephalopodvisioninvolves pages 7-8): S. D’Aniello, P. Spinelli, G. Ferrandino, K. Peterson, Mara Tsesarskia, G. Fisher, and A. D’Aniello. Cephalopod vision involves dicarboxylic amino acids: d-aspartate, l-aspartate and l-glutamate. The Biochemical journal, 386 Pt 2:331-40, Mar 2005. URL: https://doi.org/10.1042/bj20041070, doi:10.1042/bj20041070. This article has 52 citations.

14. (d’aniello2005cephalopodvisioninvolves media d49ab66e): S. D’Aniello, P. Spinelli, G. Ferrandino, K. Peterson, Mara Tsesarskia, G. Fisher, and A. D’Aniello. Cephalopod vision involves dicarboxylic amino acids: d-aspartate, l-aspartate and l-glutamate. The Biochemical journal, 386 Pt 2:331-40, Mar 2005. URL: https://doi.org/10.1042/bj20041070, doi:10.1042/bj20041070. This article has 52 citations.

15. (d’aniello2005cephalopodvisioninvolves pages 4-5): S. D’Aniello, P. Spinelli, G. Ferrandino, K. Peterson, Mara Tsesarskia, G. Fisher, and A. D’Aniello. Cephalopod vision involves dicarboxylic amino acids: d-aspartate, l-aspartate and l-glutamate. The Biochemical journal, 386 Pt 2:331-40, Mar 2005. URL: https://doi.org/10.1042/bj20041070, doi:10.1042/bj20041070. This article has 52 citations.

16. (molla2020structureandkinetic pages 21-24): G Molla, A Chaves-Sanjuan, A Savinelli, and M Nardini. Structure and kinetic properties of human d-aspartate oxidase, the enzyme-controlling d-aspartate levels in brain. Unknown journal, 2020.

17. (usiello2020newevidenceon pages 10-12): Alessandro Usiello, Maria Maddalena Di Fiore, Arianna De Rosa, Sara Falvo, Francesco Errico, Alessandra Santillo, Tommaso Nuzzo, and Gabriella Chieffi Baccari. New evidence on the role of d-aspartate metabolism in regulating brain and endocrine system physiology: from preclinical observations to clinical applications. International Journal of Molecular Sciences, 21:8718, Nov 2020. URL: https://doi.org/10.3390/ijms21228718, doi:10.3390/ijms21228718. This article has 55 citations.

18. (garofalo2024decreasedfreedaspartate pages 2-3): Martina Garofalo, Giuseppe De Simone, Zoraide Motta, Tommaso Nuzzo, Elisa De Grandis, Claudio Bruno, Silvia Boeri, Maria Pia Riccio, Lucio Pastore, Carmela Bravaccio, Felice Iasevoli, Francesco Salvatore, Loredano Pollegioni, Francesco Errico, Andrea de Bartolomeis, and Alessandro Usiello. Decreased free d-aspartate levels in the blood serum of patients with schizophrenia. Frontiers in Psychiatry, Jul 2024. URL: https://doi.org/10.3389/fpsyt.2024.1408175, doi:10.3389/fpsyt.2024.1408175. This article has 16 citations.

19. (garofalo2024decreasedfreedaspartate pages 4-6): Martina Garofalo, Giuseppe De Simone, Zoraide Motta, Tommaso Nuzzo, Elisa De Grandis, Claudio Bruno, Silvia Boeri, Maria Pia Riccio, Lucio Pastore, Carmela Bravaccio, Felice Iasevoli, Francesco Salvatore, Loredano Pollegioni, Francesco Errico, Andrea de Bartolomeis, and Alessandro Usiello. Decreased free d-aspartate levels in the blood serum of patients with schizophrenia. Frontiers in Psychiatry, Jul 2024. URL: https://doi.org/10.3389/fpsyt.2024.1408175, doi:10.3389/fpsyt.2024.1408175. This article has 16 citations.

20. (errico2015daspartateanendogenous pages 2-2): Francesco Errico, Jean-Pierre Mothet, and Alessandro Usiello. D-aspartate: an endogenous nmda receptor agonist enriched in the developing brain with potential involvement in schizophrenia. Journal of pharmaceutical and biomedical analysis, 116:7-17, Dec 2015. URL: https://doi.org/10.1016/j.jpba.2015.03.024, doi:10.1016/j.jpba.2015.03.024. This article has 72 citations and is from a peer-reviewed journal.

21. (errico2018theemergingrole pages 1-2): Francesco Errico, Tommaso Nuzzo, Massimo Carella, Alessandro Bertolino, and Alessandro Usiello. The emerging role of altered d-aspartate metabolism in schizophrenia: new insights from preclinical models and human studies. Frontiers in Psychiatry, Nov 2018. URL: https://doi.org/10.3389/fpsyt.2018.00559, doi:10.3389/fpsyt.2018.00559. This article has 51 citations.

22. (falvo2024newinsightsinto pages 1-2): Sara Falvo, Alessandra Santillo, Maria Maddalena Di Fiore, Massimo Venditti, Giulia Grillo, Debora Latino, Isabella Baccari, Giuseppe Petito, and Gabriella Chieffi Baccari. New insights into d-aspartate signaling in testicular activity. Cells, 13:1400, Aug 2024. URL: https://doi.org/10.3390/cells13161400, doi:10.3390/cells13161400. This article has 7 citations.

23. (falvo2024newinsightsinto pages 2-3): Sara Falvo, Alessandra Santillo, Maria Maddalena Di Fiore, Massimo Venditti, Giulia Grillo, Debora Latino, Isabella Baccari, Giuseppe Petito, and Gabriella Chieffi Baccari. New insights into d-aspartate signaling in testicular activity. Cells, 13:1400, Aug 2024. URL: https://doi.org/10.3390/cells13161400, doi:10.3390/cells13161400. This article has 7 citations.

24. (molla2020structureandkinetic pages 16-18): G Molla, A Chaves-Sanjuan, A Savinelli, and M Nardini. Structure and kinetic properties of human d-aspartate oxidase, the enzyme-controlling d-aspartate levels in brain. Unknown journal, 2020.

25. (katane2015identificationofnovel pages 1-3): Masumi Katane, Shota Yamada, Go Kawaguchi, Mana Chinen, Maya Matsumura, Takemi Ando, Issei Doi, Kazuki Nakayama, Yuusuke Kaneko, Satsuki Matsuda, Yasuaki Saitoh, Tetsuya Miyamoto, Masae Sekine, Noriyuki Yamaotsu, Shuichi Hirono, and Hiroshi Homma. Identification of novel d-aspartate oxidase inhibitors by in silico screening and their functional and structural characterization in vitro. Journal of medicinal chemistry, 58 18:7328-40, Sep 2015. URL: https://doi.org/10.1021/acs.jmedchem.5b00871, doi:10.1021/acs.jmedchem.5b00871. This article has 27 citations and is from a highest quality peer-reviewed journal.

Citations

1. pollegioni2021humandaspartateoxidase pages 4-5
2. tedeschi1994propertiesofthe pages 1-2
3. pollegioni2021humandaspartateoxidase pages 2-4
4. sarower2004distributionandsubstrate pages 4-5
5. pollegioni2021humandaspartateoxidase pages 1-2
6. sarower2004distributionandsubstrate pages 1-2
7. garofalo2024decreasedfreedaspartate pages 2-3
8. garofalo2024decreasedfreedaspartate pages 4-6
9. usiello2020newevidenceon pages 1-3
10. errico2015daspartateanendogenous pages 2-2
11. katane2015identificationofnovel pages 1-3
12. molla2020structureandkinetic pages 1-5
13. falvo2024newinsightsinto pages 1-2
14. puggioni2020biochemicalcharacterizationof pages 1-2
15. sarower2004distributionandsubstrate pages 3-4
16. molla2020structureandkinetic pages 11-13
17. molla2020structureandkinetic pages 21-24
18. usiello2020newevidenceon pages 10-12
19. errico2018theemergingrole pages 1-2
20. falvo2024newinsightsinto pages 2-3
21. molla2020structureandkinetic pages 16-18
22. https://doi.org/10.3389/fpsyt.2024.1408175;
23. https://doi.org/10.3390/cells13161400;
24. https://doi.org/10.1021/acs.jmedchem.5b00871;
25. https://doi.org/10.1042/bj20041070;
26. https://doi.org/10.1016/0167-4838(94
27. https://doi.org/10.3389/fmolb.2021.689719;
28. https://doi.org/10.1042/bj20041070
29. https://doi.org/10.3389/fmolb.2021.689719
30. https://doi.org/10.3389/fpsyt.2024.1408175
31. https://doi.org/10.3390/cells13161400
32. https://doi.org/10.1021/acs.jmedchem.5b00871
33. https://doi.org/10.1042/bj20041070,
34. https://doi.org/10.1016/j.bbapap.2020.140472,
35. https://doi.org/10.3390/ijms21228718,
36. https://doi.org/10.3389/fmolb.2021.689719,
37. https://doi.org/10.3389/fpsyt.2024.1408175,
38. https://doi.org/10.1016/j.jpba.2015.03.024,
39. https://doi.org/10.3389/fpsyt.2018.00559,
40. https://doi.org/10.3390/cells13161400,
41. https://doi.org/10.1021/acs.jmedchem.5b00871,

DDO (D-aspartate oxidase) — Octopus vulgaris — Research Notes

Gene Overview

DDO (D-aspartate oxidase, EC 1.4.3.1) is a FAD-dependent flavoenzyme that selectively catalyzes
the oxidative deamination of acidic D-amino acids, primarily D-aspartate and D-glutamate. It is
one of the best biochemically characterized cephalopod enzymes, thanks to extensive work by the
D'Aniello lab at Stazione Zoologica A. Dohrn, Naples.

UniProt: A0A7E6FSU6 (Swiss-Prot reviewed), 336 AA, monomer, MW ~37 kDa.

Key Findings from Literature

Enzyme Properties (PMID:7915543)

• Purified from O. vulgaris hepatopancreas
• Monomer of Mr 37,000 containing 1 mol FAD per mol protein
• Two enzyme forms: active (FAD-bound) and inactive (6-OH-FAD-bound, artifact of purification)
• N-terminal sequence shows similarity to bovine D-aspartate oxidase and porcine D-amino acid oxidase
• Kinetic parameters: KM 4.3 mM for D-Asp, 9.7 mM for D-Glu, 47.7 mM for NMDA
• Two active-site residues with pKa 7.1 and 9.1 critical for catalysis
• kcat 6.8 s-1 with D-Asp, 11 s-1 with D-Glu

Substrate Specificity (PMID:8103425)

• D-AspO specifically oxidizes: D-Asp, D-Glu, D-Asn, D-Gln, D-Asp-dimethylester, N-methyl-D-Asp
• D-Pro, D-Leu, D-Ala, D-Met oxidized at very low rate (0.2-0.6% of D-Asp rate)
• All L-amino acids NOT oxidized — strict D-stereoselectivity
• Clearly distinct from D-amino acid oxidase (DAO) which handles neutral/hydrophobic D-amino acids

Biological Role — D-amino acid detoxification (PMID:7903300)

• D-amino acids administered to animals are absorbed and oxidized by D-AspO and DAO in tissues
• Inverse relationship: younger animals have less oxidase → more free D-amino acids
• If not metabolized, D-amino acids accumulate and cause toxicity (suppress enzyme synthesis, inhibit growth)
• Enzyme is induced in young rats when mothers ingest D-Asp during pregnancy/suckling
• Biological role: detoxification of D-amino acids that accumulate during aging

D-Aspartate in Cephalopod Nervous Tissue (PMID:8446003)

• Free D-Asp found at high concentrations in CNS of cephalopods (O. vulgaris, L. vulgaris, S. officinalis) and Aplysia
• D-Asp was 8.3% of total aspartate in Aplysia ganglia
• No other free D-amino acids detected in nervous tissue
• Suggests D-Asp may have a specific neurological function in molluscan CNS
• D-AspO from Octopus was used as analytical tool to measure D-Asp levels

NMDA Receptor Context (PMID:18703100)

• NMDA receptors are present in Octopus olfactory lobes
• NMDA enhances GnRH mRNA expression in dose-response manner
• L-glutamate/NMDA/NO pathway controls reproductive maturation in O. vulgaris
• D-aspartate (the DDO substrate) can act as NMDA receptor agonist
• DDO therefore plays a role in modulating NMDA receptor-mediated signaling by regulating D-Asp levels

Use as Analytical Tool (PMID:2306473)

• Octopus D-AspO widely used as analytical reagent for measuring D-amino acids
• Can detect 0.05 nmol D-amino acid in presence of 20 µmol L-amino acids (ratio 0.00025%)

Summary of Core Functions

1. Catalytic function: FAD-dependent oxidative deamination of D-Asp and D-Glu (EC 1.4.3.1)
2. Detoxification: Protection against toxicity of D-amino acids
3. Neuromodulation: Regulation of D-Asp levels in CNS, thereby modulating NMDA receptor signaling
4. Subcellular location: Peroxisome matrix (by similarity to mammalian orthologs)
5. Developmental regulation: Expression increases postnatally in liver/kidney