HAAO is a cytosolic, non-heme Fe(II)-dependent dioxygenase that opens the ring of 3-hydroxyanthranilate to form 2-amino-3-carboxymuconate semialdehyde (ACMS). Its monomeric bicupin structure coordinates catalytic iron through two histidines and a glutamate. ACMS can spontaneously cyclize to quinolinate, supplying a precursor for NAD+ synthesis through the kynurenine pathway of tryptophan degradation. ACMSD can divert this intermediate by decarboxylation. Biallelic loss-of-function HAAO variants impair NAD+ synthesis and cause congenital malformations.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0019805 quinolinate biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: HAAO supplies the immediate precursor for quinolinate biosynthesis. Reason: Retained PAINT IBD PTN000398325 includes human HAAO itself. HAAO catalyzes ACMS production before spontaneous quinolinate formation; self-donation is legitimate experimental grounding. Supporting Evidence: file:human/HAAO/HAAO-uniprot.txt file:interpro/panther/PTHR15497/PTHR15497-paint.tsv |
| GO:0034354 'de novo' NAD+ biosynthetic process from L-tryptophan | IBA GO_REF:0000033 | MODIFY | Summary: Phylogenetic (IBA) propagation of de novo NAD+ biosynthesis from L-tryptophan. This is a core pathway-level role for HAAO, which generates quinolinate, the precursor of de novo NAD+. Directly supported by PMID:28792876 (HAAO loss-of-function causes systemic NAD deficiency). Reason: HAAO catalyzes a step in tryptophan-derived NAD synthesis. QuickGO marks the incoming term obsolete while the inspected OLS version remains active; neither service supplied an official replacement. Preserve the original ID and label, and recommend active NAD+ biosynthetic process GO:0009435 as an authored biological replacement already supported on this gene. ACMS is the direct enzyme product; quinolinate forms subsequently by spontaneous cyclization. Proposed replacements: NAD+ biosynthetic process Supporting Evidence: file:human/HAAO/HAAO-uniprot.txt file:interpro/panther/PTHR15497/PTHR15497-paint.tsv file:human/HAAO/HAAO-source-evidence.json |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: Refine the cytoplasmic assertion to the established cytosolic location. Reason: Cytosol is the more precise supported compartment already annotated on HAAO. Reactome places its catalytic reaction in cytosol; retain the original source qualifier while proposing this refinement. Proposed replacements: cytosol Supporting Evidence: Reactome:R-HSA-71218 file:human/HAAO/HAAO-uniprot.txt file:interpro/panther/PTHR15497/PTHR15497-paint.tsv |
| GO:0000334 3-hydroxyanthranilate 3,4-dioxygenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited dioxygenase activity agrees with direct human enzyme evidence. Reason: The retained ancestral catalytic assertion agrees with the demonstrated human enzyme reaction. Literal PAINT and human identity were checked; no tree/MSA replay is claimed. Supporting Evidence: file:human/HAAO/HAAO-uniprot.txt file:interpro/panther/PTHR15497/PTHR15497-paint.tsv |
| GO:0000334 3-hydroxyanthranilate 3,4-dioxygenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The historical electronic mapping identifies the established HAAO catalytic activity. Reason: The combined electronic mapping agrees with demonstrated oxidative cleavage of 3-hydroxyanthranilate to ACMS. This historical mapping is retained alongside its current combined-source context; see the input audit. |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | MODIFY | Summary: Ferrous iron binding is a more informative description of the catalytic cofactor. Reason: The binding assertion is correct. Refine it to ferrous iron binding, the experimentally supported catalytic-cofactor function already represented by the human biochemical and structural evidence. Cofactor binding supports the single catalytic core rather than an independent core activity. Proposed replacements: ferrous iron binding |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | MODIFY | Summary: Refine the cytoplasmic assertion to the established cytosolic location. Reason: Cytosol is the more precise supported compartment already annotated on HAAO. Reactome places its catalytic reaction in cytosol; retain the original source qualifier while proposing this refinement. Proposed replacements: cytosol Supporting Evidence: Reactome:R-HSA-71218 file:human/HAAO/HAAO-uniprot.txt |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: The historical UniProt location mapping supports cytosolic HAAO. Reason: The UniProt mapping agrees with curated cytosolic HAAO and the retained human Reactome reaction. This historical mapping is retained alongside its current combined-source context; see the input audit. Supporting Evidence: Reactome:R-HSA-71218 file:human/HAAO/HAAO-uniprot.txt |
| GO:0006569 L-tryptophan catabolic process | IEA GO_REF:0000104 | ACCEPT | Summary: HAAO catalyzes a core step of kynurenine-pathway tryptophan degradation. Reason: HAAO directly catalyzes a kynurenine-pathway step during L-tryptophan breakdown. This is a central catalytic role rather than a peripheral association. This historical mapping is retained alongside its current combined-source context; see the input audit. |
| GO:0008198 ferrous iron binding | IEA GO_REF:0000104 | ACCEPT | Summary: Ferrous iron is required for human HAAO activity. Reason: Recombinant human enzyme requires Fe(II), supporting the specific electronic cofactor-binding assertion. |
| GO:0019805 quinolinate biosynthetic process | IEA GO_REF:0000104 | ACCEPT | Summary: ACMS production is HAAO's catalytic contribution to quinolinate biosynthesis. Reason: The enzyme makes ACMS, which spontaneously cyclizes to quinolinate. Its catalytic step contributes directly to this biosynthetic pathway. |
| GO:0034354 'de novo' NAD+ biosynthetic process from L-tryptophan | IEA GO_REF:0000104 | MODIFY | Summary: The NAD biosynthesis role is supported; use an active process term. Reason: HAAO catalyzes a step in tryptophan-derived NAD synthesis. QuickGO marks the incoming term obsolete while the inspected OLS version remains active; neither service supplied an official replacement. Preserve the original ID and label, and recommend active NAD+ biosynthetic process GO:0009435 as an authored biological replacement already supported on this gene. ACMS is the direct enzyme product; quinolinate forms subsequently by spontaneous cyclization. Proposed replacements: NAD+ biosynthetic process Supporting Evidence: file:human/HAAO/HAAO-uniprot.txt file:human/HAAO/HAAO-source-evidence.json |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | MODIFY | Summary: Ferrous iron binding specifies the relevant metal-cofactor function. Reason: The binding assertion is correct. Refine it to ferrous iron binding, the experimentally supported catalytic-cofactor function already represented by the human biochemical and structural evidence. Cofactor binding supports the single catalytic core rather than an independent core activity. Proposed replacements: ferrous iron binding |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | KEEP AS NON CORE | Summary: The HAAO–GAD1 interaction is supported but has no established specific molecular role. Reason: IntAct IM-16520-414 records human HAAO–GAD1 association by two-hybrid pooling in this paper. Retain supported binding without inventing a specific function. |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | KEEP AS NON CORE | Summary: Curated HAAO–POT1 experiment records support a non-core physical association. Reason: IntAct IM-24620-226 and IM-24620-719 support the association. Retain under the project instruction; assay and access limits are in the source guide. No specific molecular role is established. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the supported HAAO–GAD1 interaction with donor accession Q8IVA8 as non-core. Reason: IntAct IM-23318-38393 records validated two-hybrid association with GAD1 accession Q8IVA8. Retain this exact donor context as non-core. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: Retain the supported HAAO–GAD1 interaction from the variant-interaction study as non-core. Reason: IntAct IM-27438-3932 records HAAO–GAD1 Q99259 association by two-hybrid array. Retain the interaction without inferring a new metabolic function. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the supported HAAO–GAD1 interaction from the reference interactome as non-core. Reason: IntAct IM-25472-131849 and associated screening records support HAAO–GAD1 Q99259 association. Retain non-core binding without an unsupported specific replacement. |
| GO:0009435 NAD+ biosynthetic process | IEA GO_REF:0000041 | ACCEPT | Summary: NAD biosynthesis is a core physiological role of HAAO catalysis. Reason: NAD biosynthesis is a central physiological pathway role. Its broader scope does not make the supported process peripheral. |
| GO:0000334 3-hydroxyanthranilate 3,4-dioxygenase activity | IDA PMID:28792876 NAD Deficiency, Congenital Malformations, and Niacin Supplem... | ACCEPT | Summary: Human variant assays support the defining HAAO dioxygenase activity. Reason: HAAO variants were assayed and showed reduced catalytic activity. Retain the defining oxygenase activity; distinguish direct ACMS production from subsequent spontaneous quinolinate formation. |
| GO:0008198 ferrous iron binding | IDA PMID:28375145 Crystal structures of human 3-hydroxyanthranilate 3,4-dioxyg... | ACCEPT | Summary: Human HAAO binds catalytic iron; physiological Fe(II) and the oxidized crystal state are distinct. Reason: Human evidence establishes the catalytic iron site; active enzyme requires Fe(II). Air oxidation to Fe(III) in the reported crystal does not redefine the physiological cofactor. |
| GO:0009435 NAD+ biosynthetic process | IMP PMID:28792876 NAD Deficiency, Congenital Malformations, and Niacin Supplem... | ACCEPT | Summary: Human genetic and mouse experimental evidence support HAAO's role in NAD synthesis. Reason: Human HAAO loss-of-function and Haao-null mouse data connect the catalytic defect to NAD deficiency. Retain the core biosynthetic role. |
| GO:0019805 quinolinate biosynthetic process | IDA PMID:28792876 NAD Deficiency, Congenital Malformations, and Niacin Supplem... | ACCEPT | Summary: The HAAO reaction supplies the immediate precursor for quinolinate production. Reason: The catalytic reaction makes the immediate quinolinate precursor. Retain this biosynthetic assertion while describing ACMS as the direct enzyme product. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-71218 | ACCEPT | Summary: Reactome places the HAAO-catalyzed reaction in the cytosol. Reason: The retained human Reactome reaction explicitly describes cytosolic HAAO catalysis. It supports the modeled location; no fresh participant-graph replay is claimed. Supporting Evidence: Reactome:R-HSA-71218 file:human/HAAO/HAAO-uniprot.txt |
| GO:0000334 3-hydroxyanthranilate 3,4-dioxygenase activity | IDA PMID:12007609 Cloning of human 3-hydroxyanthranilic acid dioxygenase in Es... | ACCEPT | Summary: Purified recombinant human HAAO performs the defining dioxygenase reaction. Reason: Purified recombinant human enzyme was catalytically active with Fe(II), supporting the defining dioxygenase annotation. |
| GO:0000334 3-hydroxyanthranilate 3,4-dioxygenase activity | IDA PMID:7514594 Molecular cloning and functional expression of human 3-hydro... | ACCEPT | Summary: Functional expression establishes human HAAO catalytic activity. Reason: Human HAAO expressed in HEK293 cells was enzymatically active, supporting the defining catalytic annotation. |
| GO:0005829 cytosol | IDA PMID:7514594 Molecular cloning and functional expression of human 3-hydro... | ACCEPT | Summary: Retain established cytosolic localization with explicit curator deference. Reason: Accept established cytosolic localization with curator deference and independent Reactome/UniProt support. The cached cloning-paper abstract does not describe a localization experiment. |
| GO:0008198 ferrous iron binding | IDA PMID:12007609 Cloning of human 3-hydroxyanthranilic acid dioxygenase in Es... | ACCEPT | Summary: The human biochemical study supports the requirement for ferrous iron. Reason: The cited human recombinant enzyme requires Fe(II) for activity, supporting specific ferrous iron binding. |
| GO:0009055 electron transfer activity | NAS PMID:7514594 Molecular cloning and functional expression of human 3-hydro... | MODIFY | Summary: Represent the enzyme reaction with its established dioxygenase activity. Reason: The current definition includes enzymatic redox, so absence of a separate carrier does not itself refute the annotation. Functional expression in the cited human study supports the specific dioxygenase activity already annotated from that paper. Propose this mechanistic replacement without claiming an is_a/part_of descendant relationship or a separately established peripheral electron-transfer function. The original NAS evidence and reference remain unchanged. Proposed replacements: 3-hydroxyanthranilate 3,4-dioxygenase activity Supporting Evidence: file:human/HAAO/HAAO-uniprot.txt file:human/HAAO/HAAO-source-evidence.json directed movement of electrons from one molecular entity to another file:human/HAAO/HAAO-source-evidence.json numerous enzymatic reactions involved in metabolic pathways |
| GO:0010043 response to zinc ion | IDA PMID:12007609 Cloning of human 3-hydroxyanthranilic acid dioxygenase in Es... | UNDECIDED | Summary: A cellular zinc-response role remains unresolved by the accessible evidence. Reason: The abstract verifies Zn inhibition of purified enzyme, whereas GO requires a cell or organism response. The original cellular-process evidence remains unverified; do not infer its absence from the abstract. |
| GO:0019805 quinolinate biosynthetic process | NAS PMID:12007609 Cloning of human 3-hydroxyanthranilic acid dioxygenase in Es... | ACCEPT | Summary: The biochemical work supports HAAO's catalytic contribution to quinolinate biosynthesis. Reason: HAAO catalyzes ACMS formation upstream of spontaneous quinolinate production. NAS does not make this supported biosynthetic role non-core. |
| GO:0019805 quinolinate biosynthetic process | NAS PMID:7514594 Molecular cloning and functional expression of human 3-hydro... | ACCEPT | Summary: The cloning study supports the enzyme reaction feeding quinolinate biosynthesis. Reason: The cloning and expression study supports the enzyme reaction feeding quinolinate biosynthesis, without demonstrating enzymatic catalysis of the subsequent spontaneous cyclization. |
| GO:0046686 response to cadmium ion | IDA PMID:12007609 Cloning of human 3-hydroxyanthranilic acid dioxygenase in Es... | UNDECIDED | Summary: Cadmium-specific cellular-response evidence remains unverified. Reason: The abstract names Zn but not the second inhibitory metal. Cadmium-specific results and a cell or organism response were not verified. |
| GO:0070050 neuron cellular homeostasis | IMP PMID:2967497 3-Hydroxyanthranilate oxygenase activity is increased in the... | UNDECIDED | Summary: A direct role in neuronal homeostasis remains unresolved. Reason: The human postmortem abstract reports increased HAAO activity in Huntington disease. This correlation does not establish maintenance of a stable differentiated neuron; original causal evidence remains unverified. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the distinct HAAO–GAD1 interaction with donor accession Q99259 as non-core. Reason: IntAct IM-23318-32712 records validated two-hybrid association with GAD1 Q99259. Retain this distinct donor context alongside the Q8IVA8 context. |
| GO:0000334 3-hydroxyanthranilate 3,4-dioxygenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The current combined electronic mapping identifies the established dioxygenase activity. Reason: The newly seeded combined electronic catalytic assertion agrees with direct human enzyme evidence; retain all incoming donor and mapping identifiers. |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: The current combined electronic mapping supports cytosolic HAAO. Reason: The newly seeded combined electronic cytosol assertion agrees with the independently established human location; retain its distinct source context. Supporting Evidence: Reactome:R-HSA-71218 file:human/HAAO/HAAO-uniprot.txt |
| GO:0006569 L-tryptophan catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: The current combined electronic mapping supports HAAO's direct tryptophan-catabolic role. Reason: The newly seeded combined electronic tryptophan-catabolism assertion describes the enzyme's direct kynurenine-pathway step; retain its distinct source context. |
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Q: Do the metal-inhibition experiments support a cellular zinc or cadmium response involving HAAO, beyond purified-enzyme inhibition?
Q: What direct evidence connects HAAO catalysis to maintenance of neuronal cellular homeostasis, beyond altered activity in postmortem disease tissue?
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