HGD (homogentisate 1,2-dioxygenase; EC 1.13.11.5) is a cytosolic, iron(II)-dependent ring-cleaving dioxygenase that catalyzes the third step of the tyrosine (and, upstream, phenylalanine) degradation pathway. It converts homogentisate and molecular oxygen to 4-maleylacetoacetate, opening the aromatic ring. Each subunit binds one catalytic Fe(II) ion (coordinated by His335, Glu341 and His371), and the active enzyme assembles as a homohexamer arranged as a dimer of trimers. HGD is expressed most highly in liver, kidney, prostate and intestine, consistent with its role in amino-acid catabolism. Loss-of-function variants in HGD cause alkaptonuria, an autosomal recessive inborn error of metabolism in which homogentisic acid accumulates; its oxidized, polymerized form deposits as ochronotic pigment in cartilage and other connective tissues, producing dark urine, ochronotic osteoarthropathy/spondyloarthropathy, and later cardiac-valve and renal disease.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004411 homogentisate 1,2-dioxygenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. HGD catalyzes homogentisate + O2 -> 4-maleylacetoacetate (EC 1.13.11.5, RHEA:15449). The phylogenetic (IBA) inference is at the correct level of specificity and matches the experimentally established activity. Reason: This is the defining, experimentally validated activity of HGD, consistent across IBA, IEA, IMP and TAS evidence and confirmed structurally (PMID:10876237). Supporting Evidence: PMID:8782815 resulting from loss of homogentisate 1,2 dioxygenase (HGO) activity |
| GO:0006559 L-phenylalanine catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: HGD acts in the phenylalanine degradation pathway (UniPathway UPA00139: acetoacetate and fumarate from L-phenylalanine, step 4/6). Phenylalanine is catabolized via tyrosine to homogentisate, HGD's substrate. Reason: Correct pathway-level involvement; homogentisate is a shared intermediate of phenylalanine and tyrosine catabolism, both of which route through HGD. Supporting Evidence: PMID:8782815 an intermediary product of the catabolism of tyrosine and phenylalanine |
| GO:0004411 homogentisate 1,2-dioxygenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the core dioxygenase activity via InterPro IPR005708, ARBA, RHEA:15449 and EC:1.13.11.5. Fully consistent with experimental evidence. Reason: Duplicate of the experimentally supported core MF; the IEA mapping is at the correct specificity for the homogentisate dioxygenase family signature. |
| GO:0006559 L-phenylalanine catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment (InterPro IPR005708 + UniPathway UPA00139) of phenylalanine catabolic-process involvement. Consistent with the pathway role. Reason: Correct pathway membership; duplicate of the IBA/TAS phenylalanine catabolic-process annotations. |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a high-throughput fluorescence-complementation screen (HGD-TERF1 pair). Uninformative regarding molecular function and unrelated to HGD's catalytic role. Reason: Per curation guidelines the generic "protein binding" term conveys no functional information, and this hit derives from a genome-wide telomere-signaling screen with no evidence it reflects a biologically meaningful, HGD-specific partnership. Retained (not removed) as a legitimately recorded IPI, but flagged as over-annotation and non-core. Supporting Evidence: PMID:21044950 telomere signaling |
| 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 binary interactome (HGD-NTAQ1 pair; also listed in the UniProt INTERACTION block). Uninformative as a molecular-function term. Reason: "protein binding" is too generic to be a useful MF annotation; the HGD-NTAQ1 interaction is a systematic-screen datapoint, not a characterized functional module. Kept as recorded but marked over-annotated / non-core. Supporting Evidence: PMID:32296183 binary protein interactome |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Self (identical protein) interaction reflecting HGD's known homo-oligomerization. HGD assembles as a homohexamer (dimer of trimers), so self-association is a genuine structural property but not its core catalytic function. Reason: The identical-protein-binding annotation is biologically consistent with the crystallographically defined homohexamer (PMID:10876237), so it is retained; it documents the oligomeric assembly rather than the primary dioxygenase function. Supporting Evidence: PMID:25416956 human interactome PMID:10876237 Crystal structure of human homogentisate dioxygenase |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Second self-interaction datapoint (HuRI), again reflecting the homohexameric assembly of HGD. Reason: Duplicate identical-protein-binding evidence consistent with the known homohexamer; retained as a structural (non-core) property. Supporting Evidence: PMID:32296183 binary protein interactome |
| GO:0006572 L-tyrosine catabolic process | IMP PMID:36555443 Untargeted NMR Metabolomics Reveals Alternative Biomarkers a... | ACCEPT | Summary: HGD performs the ring-opening step of tyrosine catabolism, acting on homogentisate (the tyrosine-degradation intermediate). This is the most direct biological-process term for HGD. Reason: Well supported: HGA is an intermediate of tyrosine degradation and is opened/oxidized by hexameric HGD; loss of HGD activity blocks this step and causes HGA accumulation (alkaptonuria). Supporting Evidence: PMID:36555443 The aromatic ring is opened and oxidized by the hexameric homogentisate-1,2-dioxygenase (HGD) |
| GO:0004411 homogentisate 1,2-dioxygenase activity | IMP PMID:8782815 The molecular basis of alkaptonuria. | ACCEPT | Summary: Mutant-phenotype (IMP) evidence: alkaptonuria arises from loss of HGD activity, and at least one disease missense variant was shown biochemically to be loss-of-function, directly linking HGD to homogentisate 1,2-dioxygenase activity. Reason: Experimental support for the core catalytic activity from the gene-defining study; the curator read the full text and demonstrated loss-of-function. Supporting Evidence: PMID:8782815 provide biochemical evidence that at least one of these missense mutations is a loss-of-function mutation |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: HGD detected by bulk proteomics of prostatic-secretion-derived urinary exosomes. HGD is a cytosolic enzyme; this reflects co-purification in an exosome preparation rather than a functional secretory/exosomal localization. Reason: High-throughput proteomic detection in exosome fractions is common for abundant cytosolic proteins and does not establish a functional site of action. Retained as a recorded observation but explicitly non-core; the functional localization is cytosol. Supporting Evidence: PMID:23533145 exosomes isolated from expressed prostatic |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Second bulk-proteomic detection of HGD in urinary exosomes; same interpretation as PMID:23533145 (co-purification of a cytosolic enzyme). Reason: Bystander detection in an exosome proteome, not a functional localization; retained as non-core. Supporting Evidence: PMID:19056867 urinary exosomes |
| GO:0005829 cytosol | TAS Reactome:R-HSA-71164 | ACCEPT | Summary: Core cellular component. HGD is a cytosolic enzyme that carries out the homogentisate dioxygenation step in the cytoplasm. Reason: Consistent with the Reactome reaction record and the soluble cytosolic nature of the enzyme; this is the functionally relevant localization. Supporting Evidence: Reactome:R-HSA-71164 Cytosolic homogentisate 1,2-dioxygenase (HGD) catalyzes the reaction of homogentisate and |
| GO:0004411 homogentisate 1,2-dioxygenase activity | TAS PMID:8782815 The molecular basis of alkaptonuria. | ACCEPT | Summary: Author-statement (TAS) support for the core dioxygenase activity from the gene-defining alkaptonuria study. Reason: Duplicate of the core MF with independent (TAS) evidence; fully consistent with all other lines of evidence. Supporting Evidence: PMID:8782815 resulting from loss of homogentisate 1,2 dioxygenase (HGO) activity |
| GO:0006559 L-phenylalanine catabolic process | TAS PMID:8782815 The molecular basis of alkaptonuria. | ACCEPT | Summary: Author-statement support for HGD's role in phenylalanine catabolism (homogentisate is a shared Phe/Tyr catabolic intermediate). Reason: Correct pathway-level involvement; consistent with the IBA/IEA phenylalanine catabolic-process annotations. Supporting Evidence: PMID:8782815 an intermediary product of the catabolism of tyrosine and phenylalanine |
| GO:0006572 L-tyrosine catabolic process | TAS PMID:8782815 The molecular basis of alkaptonuria. | ACCEPT | Summary: Author-statement support for HGD's role in tyrosine catabolism; duplicate of the IMP tyrosine-catabolic-process annotation. Reason: The gene-defining study places HGD in tyrosine catabolism (homogentisate is a tyrosine-degradation intermediate); consistent core biological process. Supporting Evidence: PMID:8782815 an intermediary product of the catabolism of tyrosine and phenylalanine |
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)