HAAO

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0019805 quinolinate biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) propagation of the quinolinate biosynthetic process. This is a core biological role of HAAO: its product ACMS cyclizes spontaneously to quinolinate. Consistent with experimental annotations (PMID:7514594, PMID:12007609, PMID:28792876) and UniProt PATHWAY "quinolinate from L-kynurenine: step 3/3".
GO:0034354 'de novo' NAD+ biosynthetic process from L-tryptophan	IBA GO_REF:0000033	ACCEPT	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).
GO:0005737 cytoplasm	IBA GO_REF:0000033	MODIFY	Summary: Phylogenetic (IBA) cytoplasm annotation. Correct but less specific than the experimentally supported cytosol (GO:0005829). Retained as a non-core, less-informative parent of the cytosol location. Proposed replacements: cytosol
GO:0000334 3-hydroxyanthranilate 3,4-dioxygenase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) propagation of the defining catalytic molecular function. This is the core function of HAAO and is independently confirmed by multiple experimental (IDA) annotations (PMID:7514594, PMID:12007609, PMID:28792876).
GO:0000334 3-hydroxyanthranilate 3,4-dioxygenase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (ARBA/UniRule/EC-based) assignment of the defining catalytic activity. Correct; redundant with the experimental IDA annotations.
GO:0005506 iron ion binding	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO electronic assignment of iron ion binding. Correct in essence but less specific than the experimentally demonstrated ferrous (Fe2+) iron binding (GO:0008198, IDA from PMID:12007609 and PMID:28375145). The enzyme strictly requires Fe(II). Proposed replacements: ferrous iron binding
GO:0005737 cytoplasm	IEA GO_REF:0000120	MODIFY	Summary: Electronic cytoplasm location. Correct but less specific than the experimentally supported cytosol (GO:0005829, IDA PMID:7514594). Proposed replacements: cytosol
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Electronic (UniProt subcellular location) cytosol annotation. Correct and consistent with the experimental IDA cytosol annotation (PMID:7514594).
GO:0006569 L-tryptophan catabolic process	IEA GO_REF:0000104	KEEP AS NON CORE	Summary: Electronic (UniRule) assignment placing HAAO in tryptophan catabolism. Biologically correct: 3-HAO is a kynurenine-pathway enzyme of tryptophan degradation. Retained as an accurate higher-level BP; the more specific quinolinate/NAD+ biosynthesis terms are the core annotations.
GO:0008198 ferrous iron binding	IEA GO_REF:0000104	ACCEPT	Summary: Electronic (UniRule) ferrous iron binding. Correct and matches the experimental IDA annotations (PMID:12007609, PMID:28375145). Fe(II) is the strictly required catalytic cofactor.
GO:0019805 quinolinate biosynthetic process	IEA GO_REF:0000104	ACCEPT	Summary: Electronic (UniRule) quinolinate biosynthesis. Core BP role, redundant with experimental IDA/NAS annotations.
GO:0034354 'de novo' NAD+ biosynthetic process from L-tryptophan	IEA GO_REF:0000104	ACCEPT	Summary: Electronic (UniRule) de novo NAD+ biosynthesis from tryptophan. Core pathway role, supported by the disease genetics (PMID:28792876).
GO:0046872 metal ion binding	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO generic metal ion binding. True but uninformative; the specific and experimentally supported ferrous iron binding (GO:0008198) captures the actual cofactor. Marked as over-annotated (over-general).
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a large-scale Y2H interactome map (Rual et al. 2005, CCSB-HI1). Uninformative for molecular function and not tied to any characterized complex or biological role for this cytosolic enzyme (UniProt lists only screen-derived GAD1/POT1 interactions). Not removed per policy; flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a genome-wide split-Venus BiFC telomere- interactome screen (Lee et al. 2011); the POT1 (Q9NUX5) pairing is a high-throughput screen hit with no established functional relationship to a cytosolic kynurenine-pathway enzyme. Uninformative for MF; not removed per policy; flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from the HI-II-14 systematic binary interactome map (Rolland et al. 2014). Uninformative for MF; not removed per policy; flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from an ExAC-variant Y2H interaction screen (Fragoza et al. 2019). Uninformative for MF; not removed per policy; flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from the HuRI reference binary interactome (Luck et al. 2020). Uninformative for MF; not removed per policy; flagged as over-annotated.
GO:0009435 NAD+ biosynthetic process	IEA GO_REF:0000041	KEEP AS NON CORE	Summary: Electronic (UniPathway) NAD+ biosynthetic process. Correct but less specific than the de novo NAD+ biosynthesis from L-tryptophan term (GO:0034354). Retained as a non-core, more-general parent.
GO:0000334 3-hydroxyanthranilate 3,4-dioxygenase activity	IDA PMID:28792876 NAD Deficiency, Congenital Malformations, and Niacin Supplem...	ACCEPT	Summary: Direct assay (IDA) of the defining catalytic activity: recombinant HAAO and its VCRL1 truncation variants were tested for enzyme activity, with "greatly reduced activity in vitro" for the mutants. Core molecular function.
GO:0008198 ferrous iron binding	IDA PMID:28375145 Crystal structures of human 3-hydroxyanthranilate 3,4-dioxyg...	ACCEPT	Summary: Direct assay (IDA) of ferrous iron binding, from crystal structures with native iron bound in the active site; "non-heme iron-containing, ring-cleaving extradiol dioxygenase". Core cofactor-binding function.
GO:0009435 NAD+ biosynthetic process	IMP PMID:28792876 NAD Deficiency, Congenital Malformations, and Niacin Supplem...	KEEP AS NON CORE	Summary: IMP from human/mouse loss-of-function genetics: biallelic HAAO loss-of-function causes systemic NAD deficiency ("The patients had reduced levels of circulating NAD"; Haao-null mice reproduce the phenotype). Correct but less specific than the de novo NAD+ from L-tryptophan term (GO:0034354). Retained as non-core relative to the more specific term.
GO:0019805 quinolinate biosynthetic process	IDA PMID:28792876 NAD Deficiency, Congenital Malformations, and Niacin Supplem...	ACCEPT	Summary: IDA supporting quinolinate biosynthesis (enzyme assay of HAAO forming the quinolinate precursor). Core biological process for HAAO.
GO:0005829 cytosol	TAS Reactome:R-HSA-71218	ACCEPT	Summary: Reactome TAS cytosol location for the 3-hydroxyanthranilate + O2 reaction ("Cytosolic 3-hydroxyanthranilate oxygenase ..."). Consistent with the experimental IDA cytosol annotation. Core localization.
GO:0000334 3-hydroxyanthranilate 3,4-dioxygenase activity	IDA PMID:12007609 Cloning of human 3-hydroxyanthranilic acid dioxygenase in Es...	ACCEPT	Summary: Direct assay (IDA) of the catalytic activity of purified recombinant human 3-HAO expressed in E. coli, converting 3-hydroxyanthranilic acid to quinolinic acid. Core molecular function.
GO:0000334 3-hydroxyanthranilate 3,4-dioxygenase activity	IDA PMID:7514594 Molecular cloning and functional expression of human 3-hydro...	ACCEPT	Summary: Direct assay (IDA) from the original cloning/functional expression of human 3-HAO; recombinant enzyme catalyzes quinolinate synthesis with Km(3-HANA) ~2 microM. Core molecular function.
GO:0005829 cytosol	IDA PMID:7514594 Molecular cloning and functional expression of human 3-hydro...	ACCEPT	Summary: IDA cytosol localization from the cloning/expression study; matches UniProt "Cytoplasm, cytosol" and Reactome. Core localization.
GO:0008198 ferrous iron binding	IDA PMID:12007609 Cloning of human 3-hydroxyanthranilic acid dioxygenase in Es...	ACCEPT	Summary: IDA ferrous iron binding: enzymatic activity "can occur only in the presence of Fe(II)"; other metals do not support catalysis. Core cofactor-binding function.
GO:0009055 electron transfer activity	NAS PMID:7514594 Molecular cloning and functional expression of human 3-hydro...	MARK AS OVER ANNOTATED	Summary: NAS "electron transfer activity" is mechanistically incorrect for HAAO: it is a non-heme Fe(II) extradiol dioxygenase that incorporates both atoms of O2 into the substrate during ring cleavage (PMID:28375145), not an electron carrier. This is an author-statement over-annotation superseded by the structural/mechanistic characterization. Marked as over-annotated (retained per NAS/non-experimental over-annotation policy).
GO:0010043 response to zinc ion	IDA PMID:12007609 Cloning of human 3-hydroxyanthranilic acid dioxygenase in Es...	MARK AS OVER ANNOTATED	Summary: IDA "response to zinc ion" derives from the in vitro observation that Zn2+ inhibits 3-HAO catalysis ("Zn2+, could be of physiological relevance" as an inhibitor). Inhibitor sensitivity of a purified enzyme is not evidence that HAAO participates in a cellular response-to-zinc process; this is an over-interpretation of an inhibition assay. Kept (experimental IDA) but flagged as over-annotated.
GO:0019805 quinolinate biosynthetic process	NAS PMID:12007609 Cloning of human 3-hydroxyanthranilic acid dioxygenase in Es...	ACCEPT	Summary: NAS quinolinate biosynthesis; correct core BP, redundant with the experimental IDA annotations for the same term.
GO:0019805 quinolinate biosynthetic process	NAS PMID:7514594 Molecular cloning and functional expression of human 3-hydro...	ACCEPT	Summary: NAS quinolinate biosynthesis from the original cloning paper; correct core BP, redundant with the experimental IDA annotations.
GO:0046686 response to cadmium ion	IDA PMID:12007609 Cloning of human 3-hydroxyanthranilic acid dioxygenase in Es...	MARK AS OVER ANNOTATED	Summary: IDA "response to cadmium ion" traces to in vitro metal-inhibition testing of purified 3-HAO. As with the zinc annotation, in vitro metal inhibition is not evidence of a cellular response-to-cadmium process. Kept (experimental IDA) but flagged as over-annotated.
GO:0070050 neuron cellular homeostasis	IMP PMID:2967497 3-Hydroxyanthranilate oxygenase activity is increased in the...	KEEP AS NON CORE	Summary: Based on the observation that 3-hydroxyanthranilate oxygenase activity is increased in Huntington disease striatum (PMID:2967497), linking excess quinolinate to excitotoxic neuronal loss. This is a disease-correlation finding about pathway activity, not a demonstration that HAAO maintains neuronal homeostasis; the term is peripheral to the core enzymatic role. Retained as a non-core, disease-context process annotation.

Gene Description

Existing Annotations Review

Core Functions

Binds a catalytic ferrous (Fe2+) iron ion in the active site, strictly required for dioxygenase activity; other metals do not support catalysis and Zn2+ inhibits.

Produces the quinolinate precursor feeding de novo NAD+ biosynthesis from L-tryptophan via the kynurenine pathway; loss of HAAO causes systemic NAD deficiency and a congenital malformation syndrome.

References

📚 Additional Documentation

Notes

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