ID HGD_HUMAN Reviewed; 445 AA. AC Q93099; A8K417; B2R8Z0; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 2. DT 27-MAR-2024, entry version 206. DE RecName: Full=Homogentisate 1,2-dioxygenase; DE EC=1.13.11.5 {ECO:0000269|PubMed:8782815}; DE AltName: Full=Homogentisate oxygenase; DE AltName: Full=Homogentisic acid oxidase; DE AltName: Full=Homogentisicase; GN Name=HGD; Synonyms=HGO; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], VARIANTS AKU SER-230 AND GLY-300, VARIANT RP HIS-80, CHARACTERIZATION OF VARIANT AKU SER-230, FUNCTION, AND CATALYTIC RP ACTIVITY. RX PubMed=8782815; DOI=10.1038/ng0996-19; RA Fernandez-Canon J.M., Granadino B., Beltran-Valero de Bernabe D., RA Renedo M., Fernandez-Ruiz E., Penalva M.A., Rodriguez de Cordoba S.; RT "The molecular basis of alkaptonuria."; RL Nat. Genet. 14:19-24(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT HIS-80. RC TISSUE=Liver; RA Ramos S., Hernandez M., Rozes A., Larruga J., Gonzalez P., Cabrera V.M.; RT "Homogentisate 1,2-dioxygenase human cDNA sequence."; RL Submitted (SEP-1996) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT HIS-80. RX PubMed=9244427; DOI=10.1006/geno.1997.4805; RA Granadino B., Beltran-Valero de Bernabe D., Fernandez-Canon J.M., RA Penalva M.A., Rodriguez de Cordoba S.; RT "The human homogentisate 1,2-dioxygenase (HGO) gene."; RL Genomics 43:115-122(1997). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT HIS-80. RC TISSUE=Kidney, and Prostate; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16641997; DOI=10.1038/nature04728; RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.; RT "The DNA sequence, annotation and analysis of human chromosome 3."; RL Nature 440:1194-1198(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT HIS-80. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT HIS-80. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-98, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [9] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [10] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS), METAL-BINDING SITES, SUBUNIT, AND RP COFACTOR. RX PubMed=10876237; DOI=10.1038/76756; RA Titus G.P., Mueller H.A., Burgner J., Rodriguez de Cordoba S., RA Penalva M.A., Timm D.E.; RT "Crystal structure of human homogentisate dioxygenase."; RL Nat. Struct. Biol. 7:542-546(2000). RN [11] RP VARIANT AKU ARG-161. RX PubMed=9154114; DOI=10.1159/000134501; RA Gehrig A., Schmidt S.R., Mueller C.R., Srsen S., Srsnova K., Kress W.; RT "Molecular defects in alkaptonuria."; RL Cytogenet. Cell Genet. 76:14-16(1997). RN [12] RP VARIANTS AKU ALA-42; GLY-97; GLY-153; ILE-189; THR-216; HIS-225; SER-227 RP AND VAL-368. RX PubMed=9529363; DOI=10.1086/301805; RA Beltran-Valero de Bernabe D., Granadino B., Chiarelli I., Porfirio B., RA Mayatepek E., Aquaron R., Moore M.M., Festen J.J.M., Sanmarti R., RA Penalva M.A., de Cordoba S.R.; RT "Mutation and polymorphism analysis of the human homogentisate 1, 2- RT dioxygenase gene in alkaptonuria patients."; RL Am. J. Hum. Genet. 62:776-784(1998). RN [13] RP VARIANT AKU LYS-168. RX PubMed=9630082; DOI=10.1111/j.1399-0004.1998.tb02684.x; RA Higashino K., Liu W., Ohkawa T., Yamamoto T., Fukui K., Ohno M., RA Imanishi H., Iwasaki A., Amuro Y., Hada T.; RT "A novel point mutation associated with alkaptonuria."; RL Clin. Genet. 53:228-229(1998). RN [14] RP VARIANTS AKU GLY-60; CYS-62; ASP-122; THR-230 AND GLU-291. RX PubMed=10205262; DOI=10.1086/302376; RA Beltran-Valero de Bernabe D., Jimenez F.J., Aquaron R., RA Rodriguez de Cordoba S.; RT "Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that RT the CCC sequence motif is a mutational hot spot in the homogentisate 1,2 RT dioxygenase gene (HGO)."; RL Am. J. Hum. Genet. 64:1316-1322(1999). RN [15] RP VARIANTS AKU PRO-25 AND VAL-368. RC TISSUE=Leukocyte; RX PubMed=10340975; DOI=10.1136/bjo.83.6.680; RA Felbor U., Mutsch Y., Grehn F., Mueller C.R., Kress W.; RT "Ocular ochronosis in alkaptonuria patients carrying mutations in the RT homogentisate 1,2-dioxygenase gene."; RL Br. J. Ophthalmol. 83:680-683(1999). RN [16] RP VARIANTS AKU PRO-25; ARG-161; SER-230; ARG-270; GLY-300 AND VAL-368. RC TISSUE=Lymphocyte; RX PubMed=10482952; DOI=10.1038/sj.ejhg.5200343; RA Mueller C.R., Fregin A., Srsen S., Srsnova K., Halliger-Keller B., RA Felbor U., Seemanova E., Kress W.; RT "Allelic heterogeneity of alkaptonuria in Central Europe."; RL Eur. J. Hum. Genet. 7:645-651(1999). RN [17] RP VARIANTS AKU SER-330; VAL-368 AND ARG-371. RX PubMed=10594001; RA Beltran-Valero de Bernabe D., Peterson P., Luopajarvi K., Matintalo P., RA Alho A., Konttinen Y., Krohn K., Rodriguez de Cordoba S., Ranki A.; RT "Mutational analysis of the HGO gene in Finnish alkaptonuria patients."; RL J. Med. Genet. 36:922-923(1999). RN [18] RP VARIANTS AKU ALA-3; ALA-42; GLY-60; PRO-61; CYS-62; LEU-73; THR-92; ARG-97; RP PHE-120; TRP-120; VAL-122; ARG-123; PRO-137; LEU-158; ARG-161; ASP-168; RP LYS-168; ARG-183; GLY-187; TRP-217; LEU-225; SER-230; PRO-258; ARG-269; RP ARG-270; GLY-300; PRO-321; LEU-359; ARG-360; GLU-362; VAL-368; LEU-373 AND RP GLN-401. RX PubMed=19862842; DOI=10.1002/humu.21120; RA Vilboux T., Kayser M., Introne W., Suwannarat P., Bernardini I., RA Fischer R., O'Brien K., Kleta R., Huizing M., Gahl W.A.; RT "Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria."; RL Hum. Mutat. 30:1611-1619(2009). RN [19] RP VARIANTS AKU ARG-33; PHE-44; ARG-115; PRO-116; ALA-123; ALA-152; LEU-169; RP GLY-178; GLY-197; SER-219; ASN-276; ALA-360; ARG-361 AND HIS-374. RX PubMed=23430897; DOI=10.1007/8904_2011_68; RA Zatkova A., Sedlackova T., Radvansky J., Polakova H., Nemethova M., RA Aquaron R., Dursun I., Usher J.L., Kadasi L.; RT "Identification of 11 novel homogentisate 1,2 dioxygenase variants in RT alkaptonuria patients and establishment of a novel LOVD-based HGD mutation RT database."; RL JIMD Rep. 4:55-65(2012). RN [20] RP VARIANTS AKU SER-227 AND ASN-369. RX PubMed=21437689; DOI=10.1007/s00296-011-1868-0; RA Al-sbou M.; RT "Novel mutations in the homogentisate 1,2 dioxygenase gene identified in RT Jordanian patients with alkaptonuria."; RL Rheumatol. Int. 32:1741-1746(2012). RN [21] RP VARIANT AKU CYS-329. RX PubMed=23353776; DOI=10.1016/j.gene.2013.01.020; RA Yang Y.J., Guo J.H., Chen W.J., Zhao R., Tang J.S., Meng X.H., Zhao L., RA Tu M., He X.Y., Wu L.Q., Zhu Y.M.; RT "First report of HGD mutations in a Chinese with alkaptonuria."; RL Gene 518:467-469(2013). RN [22] RP VARIANT [LARGE SCALE ANALYSIS] HIS-80, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [23] RP VARIANTS AKU LYS-13; ASN-18; ALA-42; GLN-53; ARG-115; PHE-120; ARG-123; RP ARG-161; LEU-169; ASN-171; GLY-197; SER-219; HIS-225; PRO-225; SER-230; RP PHE-245; ARG-270; ASN-276; GLY-300; ASP-337; LEU-359; ARG-360; ARG-361; RP VAL-368 AND HIS-374, AND VARIANT THR-172. RX PubMed=25681086; DOI=10.1007/8904_2014_380; RA Usher J.L., Ascher D.B., Pires D.E., Milan A.M., Blundell T.L., RA Ranganath L.R.; RT "Analysis of HGD gene mutations in patients with alkaptonuria from the RT United Kingdom: identification of novel mutations."; RL JIMD Rep. 24:3-11(2015). CC -!- FUNCTION: Catalyzes the conversion of homogentisate to CC maleylacetoacetate. {ECO:0000269|PubMed:8782815}. CC -!- CATALYTIC ACTIVITY: CC Reaction=homogentisate + O2 = 4-maleylacetoacetate + H(+); CC Xref=Rhea:RHEA:15449, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, CC ChEBI:CHEBI:16169, ChEBI:CHEBI:17105; EC=1.13.11.5; CC Evidence={ECO:0000269|PubMed:8782815}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15450; CC Evidence={ECO:0000305|PubMed:8782815}; CC -!- COFACTOR: CC Name=Fe cation; Xref=ChEBI:CHEBI:24875; CC Evidence={ECO:0000269|PubMed:10876237}; CC -!- PATHWAY: Amino-acid degradation; L-phenylalanine degradation; CC acetoacetate and fumarate from L-phenylalanine: step 4/6. CC -!- SUBUNIT: Homohexamer arranged as a dimer of trimers. CC {ECO:0000269|PubMed:10876237}. CC -!- INTERACTION: CC Q93099; Q93099: HGD; NbExp=4; IntAct=EBI-3907760, EBI-3907760; CC Q93099; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-3907760, EBI-741158; CC Q93099; P54274: TERF1; NbExp=2; IntAct=EBI-3907760, EBI-710997; CC -!- TISSUE SPECIFICITY: Highest expression in the prostate, small CC intestine, colon, kidney and liver. CC -!- DISEASE: Alkaptonuria (AKU) [MIM:203500]: An autosomal recessive error CC of metabolism characterized by an increase in the level of homogentisic CC acid. The clinical manifestations are urine that turns dark on standing CC and alkalinization, black ochronotic pigmentation of cartilage and CC collagenous tissues, and spine arthritis. {ECO:0000269|PubMed:10205262, CC ECO:0000269|PubMed:10340975, ECO:0000269|PubMed:10482952, CC ECO:0000269|PubMed:10594001, ECO:0000269|PubMed:19862842, CC ECO:0000269|PubMed:21437689, ECO:0000269|PubMed:23353776, CC ECO:0000269|PubMed:23430897, ECO:0000269|PubMed:25681086, CC ECO:0000269|PubMed:8782815, ECO:0000269|PubMed:9154114, CC ECO:0000269|PubMed:9529363, ECO:0000269|PubMed:9630082}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the homogentisate dioxygenase family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U63008; AAB16836.1; -; mRNA. DR EMBL; Z75048; CAA99340.1; -; mRNA. DR EMBL; AF000573; AAC51650.1; -; Genomic_DNA. DR EMBL; AF045167; AAC02698.1; -; mRNA. DR EMBL; AK290782; BAF83471.1; -; mRNA. DR EMBL; AK313563; BAG36337.1; -; mRNA. DR EMBL; AC126182; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC133474; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471052; EAW79524.1; -; Genomic_DNA. DR EMBL; BC071757; AAH71757.1; -; mRNA. DR CCDS; CCDS3000.1; -. DR RefSeq; NP_000178.2; NM_000187.3. DR PDB; 1EY2; X-ray; 2.30 A; A=1-445. DR PDB; 1EYB; X-ray; 1.90 A; A=1-445. DR PDBsum; 1EY2; -. DR PDBsum; 1EYB; -. DR AlphaFoldDB; Q93099; -. DR SMR; Q93099; -. DR BioGRID; 109329; 8. DR IntAct; Q93099; 6. DR MINT; Q93099; -. DR STRING; 9606.ENSP00000283871; -. DR GlyGen; Q93099; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q93099; -. DR PhosphoSitePlus; Q93099; -. DR BioMuta; HGD; -. DR jPOST; Q93099; -. DR MassIVE; Q93099; -. DR MaxQB; Q93099; -. DR PaxDb; 9606-ENSP00000283871; -. DR PeptideAtlas; Q93099; -. DR ProteomicsDB; 75725; -. DR Antibodypedia; 32802; 276 antibodies from 30 providers. DR DNASU; 3081; -. DR Ensembl; ENST00000283871.10; ENSP00000283871.5; ENSG00000113924.12. DR GeneID; 3081; -. DR KEGG; hsa:3081; -. DR MANE-Select; ENST00000283871.10; ENSP00000283871.5; NM_000187.4; NP_000178.2. DR UCSC; uc003edw.4; human. DR AGR; HGNC:4892; -. DR CTD; 3081; -. DR DisGeNET; 3081; -. DR GeneCards; HGD; -. DR GeneReviews; HGD; -. DR HGNC; HGNC:4892; HGD. DR HPA; ENSG00000113924; Group enriched (kidney, liver). DR MalaCards; HGD; -. DR MIM; 203500; phenotype. DR MIM; 607474; gene. DR neXtProt; NX_Q93099; -. DR OpenTargets; ENSG00000113924; -. DR Orphanet; 56; Alkaptonuria. DR PharmGKB; PA29268; -. DR VEuPathDB; HostDB:ENSG00000113924; -. DR eggNOG; KOG1417; Eukaryota. DR GeneTree; ENSGT00390000004601; -. DR HOGENOM; CLU_027174_0_0_1; -. DR InParanoid; Q93099; -. DR OMA; MLPHGPD; -. DR OrthoDB; 525at2759; -. DR PhylomeDB; Q93099; -. DR TreeFam; TF300490; -. DR BioCyc; MetaCyc:HS03728-MONOMER; -. DR BRENDA; 1.13.11.5; 2681. DR PathwayCommons; Q93099; -. DR Reactome; R-HSA-8963684; Tyrosine catabolism. DR SignaLink; Q93099; -. DR UniPathway; UPA00139; UER00339. DR BioGRID-ORCS; 3081; 13 hits in 1144 CRISPR screens. DR ChiTaRS; HGD; human. DR EvolutionaryTrace; Q93099; -. DR GenomeRNAi; 3081; -. DR Pharos; Q93099; Tbio. DR PRO; PR:Q93099; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; Q93099; Protein. DR Bgee; ENSG00000113924; Expressed in right lobe of liver and 141 other cell types or tissues. DR ExpressionAtlas; Q93099; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0004411; F:homogentisate 1,2-dioxygenase activity; IMP:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0006559; P:L-phenylalanine catabolic process; IBA:GO_Central. DR GO; GO:0006572; P:tyrosine catabolic process; TAS:ProtInc. DR CDD; cd07000; cupin_HGO_N; 1. DR Gene3D; 2.60.120.10; Jelly Rolls; 1. DR InterPro; IPR046451; HgmA_C. DR InterPro; IPR046452; HgmA_N. DR InterPro; IPR005708; Homogentis_dOase. DR InterPro; IPR014710; RmlC-like_jellyroll. DR InterPro; IPR011051; RmlC_Cupin_sf. DR NCBIfam; TIGR01015; hmgA; 1. DR PANTHER; PTHR11056; HOMOGENTISATE 1,2-DIOXYGENASE; 1. DR PANTHER; PTHR11056:SF0; HOMOGENTISATE 1,2-DIOXYGENASE; 1. DR Pfam; PF04209; HgmA_C; 1. DR Pfam; PF20510; HgmA_N; 1. DR SUPFAM; SSF51182; RmlC-like cupins; 1. DR Genevisible; Q93099; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Dioxygenase; Disease variant; Iron; KW Metal-binding; Oxidoreductase; Phenylalanine catabolism; KW Reference proteome; Tyrosine catabolism. FT CHAIN 1..445 FT /note="Homogentisate 1,2-dioxygenase" FT /id="PRO_0000220240" FT BINDING 335 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /evidence="ECO:0000269|PubMed:10876237, FT ECO:0007744|PDB:1EY2" FT BINDING 341 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /evidence="ECO:0000269|PubMed:10876237, FT ECO:0007744|PDB:1EY2" FT BINDING 371 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /evidence="ECO:0000269|PubMed:10876237, FT ECO:0007744|PDB:1EY2" FT MOD_RES 98 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 414 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:O09173" FT VARIANT 3 FT /note="E -> A (in AKU; dbSNP:rs200412910)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073076" FT VARIANT 13 FT /note="E -> K (in AKU; dbSNP:rs1458752246)" FT /evidence="ECO:0000269|PubMed:25681086" FT /id="VAR_073077" FT VARIANT 18 FT /note="D -> N (in AKU)" FT /evidence="ECO:0000269|PubMed:25681086" FT /id="VAR_073078" FT VARIANT 25 FT /note="L -> P (in AKU)" FT /evidence="ECO:0000269|PubMed:10340975, FT ECO:0000269|PubMed:10482952" FT /id="VAR_009618" FT VARIANT 33 FT /note="Q -> R (in AKU)" FT /evidence="ECO:0000269|PubMed:23430897" FT /id="VAR_073079" FT VARIANT 42 FT /note="E -> A (in AKU; dbSNP:rs373921680)" FT /evidence="ECO:0000269|PubMed:19862842, FT ECO:0000269|PubMed:25681086, ECO:0000269|PubMed:9529363" FT /id="VAR_005272" FT VARIANT 44 FT /note="L -> F (in AKU; dbSNP:rs1049246177)" FT /evidence="ECO:0000269|PubMed:23430897" FT /id="VAR_073080" FT VARIANT 53 FT /note="R -> Q (in AKU; dbSNP:rs200808744)" FT /evidence="ECO:0000269|PubMed:25681086" FT /id="VAR_073081" FT VARIANT 60 FT /note="W -> G (in AKU)" FT /evidence="ECO:0000269|PubMed:10205262, FT ECO:0000269|PubMed:19862842" FT /id="VAR_005273" FT VARIANT 61 FT /note="L -> P (in AKU; dbSNP:rs1324654414)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073082" FT VARIANT 62 FT /note="Y -> C (in AKU; dbSNP:rs1174584850)" FT /evidence="ECO:0000269|PubMed:10205262, FT ECO:0000269|PubMed:19862842" FT /id="VAR_005274" FT VARIANT 73 FT /note="F -> L (in AKU)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073083" FT VARIANT 80 FT /note="Q -> H (in dbSNP:rs2255543)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:8782815, FT ECO:0000269|PubMed:9244427, ECO:0000269|Ref.2, FT ECO:0000269|Ref.6, ECO:0007744|PubMed:24275569" FT /id="VAR_049353" FT VARIANT 92 FT /note="P -> T (in AKU)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073084" FT VARIANT 97 FT /note="W -> G (in AKU)" FT /evidence="ECO:0000269|PubMed:9529363" FT /id="VAR_005275" FT VARIANT 97 FT /note="W -> R (in AKU)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073085" FT VARIANT 115 FT /note="G -> R (in AKU; dbSNP:rs755734596)" FT /evidence="ECO:0000269|PubMed:23430897, FT ECO:0000269|PubMed:25681086" FT /id="VAR_073086" FT VARIANT 116 FT /note="L -> P (in AKU; dbSNP:rs569846003)" FT /evidence="ECO:0000269|PubMed:23430897" FT /id="VAR_073087" FT VARIANT 120 FT /note="C -> F (in AKU; dbSNP:rs752153829)" FT /evidence="ECO:0000269|PubMed:19862842, FT ECO:0000269|PubMed:25681086" FT /id="VAR_073088" FT VARIANT 120 FT /note="C -> W (in AKU; dbSNP:rs149165166)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073089" FT VARIANT 122 FT /note="A -> D (in AKU)" FT /evidence="ECO:0000269|PubMed:10205262" FT /id="VAR_005276" FT VARIANT 122 FT /note="A -> V (in AKU; dbSNP:rs544956641)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073090" FT VARIANT 123 FT /note="G -> A (in AKU; dbSNP:rs374473331)" FT /evidence="ECO:0000269|PubMed:23430897" FT /id="VAR_073091" FT VARIANT 123 FT /note="G -> R (in AKU; dbSNP:rs564979861)" FT /evidence="ECO:0000269|PubMed:19862842, FT ECO:0000269|PubMed:25681086" FT /id="VAR_073092" FT VARIANT 137 FT /note="L -> P (in AKU)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073093" FT VARIANT 152 FT /note="G -> A (in AKU; dbSNP:rs1553717936)" FT /evidence="ECO:0000269|PubMed:23430897" FT /id="VAR_073094" FT VARIANT 153 FT /note="D -> G (in AKU; dbSNP:rs775274569)" FT /evidence="ECO:0000269|PubMed:9529363" FT /id="VAR_005277" FT VARIANT 158 FT /note="P -> L (in AKU; dbSNP:rs375396766)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073095" FT VARIANT 161 FT /note="G -> R (in AKU; loss of activity; most prevalent FT mutation in Slovak and Czech patients; dbSNP:rs28941783)" FT /evidence="ECO:0000269|PubMed:10482952, FT ECO:0000269|PubMed:19862842, ECO:0000269|PubMed:25681086, FT ECO:0000269|PubMed:9154114" FT /id="VAR_005278" FT VARIANT 168 FT /note="E -> D (in AKU; dbSNP:rs780173554)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073096" FT VARIANT 168 FT /note="E -> K (in AKU; loss of activity; FT dbSNP:rs375283568)" FT /evidence="ECO:0000269|PubMed:19862842, FT ECO:0000269|PubMed:9630082" FT /id="VAR_009619" FT VARIANT 169 FT /note="F -> L (in AKU; dbSNP:rs756134838)" FT /evidence="ECO:0000269|PubMed:23430897, FT ECO:0000269|PubMed:25681086" FT /id="VAR_073097" FT VARIANT 171 FT /note="K -> N (in AKU)" FT /evidence="ECO:0000269|PubMed:25681086" FT /id="VAR_073098" FT VARIANT 172 FT /note="M -> T" FT /evidence="ECO:0000269|PubMed:25681086" FT /id="VAR_073099" FT VARIANT 178 FT /note="E -> G (in AKU)" FT /evidence="ECO:0000269|PubMed:23430897" FT /id="VAR_073100" FT VARIANT 183 FT /note="Q -> R (in AKU; dbSNP:rs1349543050)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073101" FT VARIANT 187 FT /note="R -> G (in AKU; dbSNP:rs756255206)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073102" FT VARIANT 189 FT /note="S -> I (in AKU)" FT /evidence="ECO:0000269|PubMed:9529363" FT /id="VAR_005279" FT VARIANT 197 FT /note="R -> G (in AKU; dbSNP:rs1414279737)" FT /evidence="ECO:0000269|PubMed:23430897, FT ECO:0000269|PubMed:25681086" FT /id="VAR_073103" FT VARIANT 216 FT /note="I -> T (in AKU; dbSNP:rs767201131)" FT /evidence="ECO:0000269|PubMed:9529363" FT /id="VAR_005280" FT VARIANT 217 FT /note="G -> W (in AKU)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073104" FT VARIANT 219 FT /note="N -> S (in AKU)" FT /evidence="ECO:0000269|PubMed:23430897, FT ECO:0000269|PubMed:25681086" FT /id="VAR_073105" FT VARIANT 225 FT /note="R -> H (in AKU; dbSNP:rs562853291)" FT /evidence="ECO:0000269|PubMed:25681086, FT ECO:0000269|PubMed:9529363" FT /id="VAR_005281" FT VARIANT 225 FT /note="R -> L (in AKU)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073106" FT VARIANT 225 FT /note="R -> P (in AKU; dbSNP:rs562853291)" FT /evidence="ECO:0000269|PubMed:25681086" FT /id="VAR_073107" FT VARIANT 227 FT /note="F -> S (in AKU; dbSNP:rs1941093400)" FT /evidence="ECO:0000269|PubMed:21437689, FT ECO:0000269|PubMed:9529363" FT /id="VAR_005282" FT VARIANT 230 FT /note="P -> S (in AKU; complete loss of activity; FT dbSNP:rs28942100)" FT /evidence="ECO:0000269|PubMed:10482952, FT ECO:0000269|PubMed:19862842, ECO:0000269|PubMed:25681086, FT ECO:0000269|PubMed:8782815" FT /id="VAR_005283" FT VARIANT 230 FT /note="P -> T (in AKU)" FT /evidence="ECO:0000269|PubMed:10205262" FT /id="VAR_005284" FT VARIANT 245 FT /note="V -> F (in AKU)" FT /evidence="ECO:0000269|PubMed:25681086" FT /id="VAR_073108" FT VARIANT 258 FT /note="Q -> P (in AKU; dbSNP:rs759843592)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073109" FT VARIANT 269 FT /note="H -> R (in AKU; dbSNP:rs756522409)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073110" FT VARIANT 270 FT /note="G -> R (in AKU; dbSNP:rs120074174)" FT /evidence="ECO:0000269|PubMed:10482952, FT ECO:0000269|PubMed:19862842, ECO:0000269|PubMed:25681086" FT /id="VAR_009620" FT VARIANT 276 FT /note="K -> N (in AKU; dbSNP:rs1160502581)" FT /evidence="ECO:0000269|PubMed:23430897, FT ECO:0000269|PubMed:25681086" FT /id="VAR_073111" FT VARIANT 291 FT /note="D -> E (in AKU; dbSNP:rs754428438)" FT /evidence="ECO:0000269|PubMed:10205262" FT /id="VAR_005285" FT VARIANT 300 FT /note="V -> G (in AKU; dbSNP:rs120074170)" FT /evidence="ECO:0000269|PubMed:10482952, FT ECO:0000269|PubMed:19862842, ECO:0000269|PubMed:25681086, FT ECO:0000269|PubMed:8782815" FT /id="VAR_005286" FT VARIANT 321 FT /note="R -> P (in AKU)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073112" FT VARIANT 329 FT /note="F -> C (in AKU)" FT /evidence="ECO:0000269|PubMed:23353776" FT /id="VAR_073113" FT VARIANT 330 FT /note="R -> S (in AKU; dbSNP:rs120074171)" FT /evidence="ECO:0000269|PubMed:10594001" FT /id="VAR_008744" FT VARIANT 337 FT /note="N -> D (in AKU)" FT /evidence="ECO:0000269|PubMed:25681086" FT /id="VAR_073114" FT VARIANT 359 FT /note="P -> L (in AKU; dbSNP:rs764037565)" FT /evidence="ECO:0000269|PubMed:19862842, FT ECO:0000269|PubMed:25681086" FT /id="VAR_073115" FT VARIANT 360 FT /note="G -> A (in AKU)" FT /evidence="ECO:0000269|PubMed:23430897" FT /id="VAR_073116" FT VARIANT 360 FT /note="G -> R (in AKU; dbSNP:rs368717991)" FT /evidence="ECO:0000269|PubMed:19862842, FT ECO:0000269|PubMed:25681086" FT /id="VAR_073117" FT VARIANT 361 FT /note="G -> R (in AKU; dbSNP:rs765219004)" FT /evidence="ECO:0000269|PubMed:23430897, FT ECO:0000269|PubMed:25681086" FT /id="VAR_073118" FT VARIANT 362 FT /note="G -> E (in AKU)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073119" FT VARIANT 368 FT /note="M -> V (in AKU; loss of activity; FT dbSNP:rs120074173)" FT /evidence="ECO:0000269|PubMed:10340975, FT ECO:0000269|PubMed:10482952, ECO:0000269|PubMed:10594001, FT ECO:0000269|PubMed:19862842, ECO:0000269|PubMed:25681086, FT ECO:0000269|PubMed:9529363" FT /id="VAR_005287" FT VARIANT 369 FT /note="T -> N (in AKU; dbSNP:rs765912447)" FT /evidence="ECO:0000269|PubMed:21437689" FT /id="VAR_073120" FT VARIANT 371 FT /note="H -> R (in AKU; dbSNP:rs120074172)" FT /evidence="ECO:0000269|PubMed:10594001" FT /id="VAR_008745" FT VARIANT 373 FT /note="P -> L (in AKU; dbSNP:rs138558042)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073121" FT VARIANT 374 FT /note="D -> H (in AKU; dbSNP:rs981454067)" FT /evidence="ECO:0000269|PubMed:23430897, FT ECO:0000269|PubMed:25681086" FT /id="VAR_073122" FT VARIANT 401 FT /note="E -> Q (in AKU; dbSNP:rs767159114)" FT /evidence="ECO:0000269|PubMed:19862842" FT /id="VAR_073123" FT CONFLICT 383 FT /note="K -> R (in Ref. 4; BAF83471)" FT /evidence="ECO:0000305" FT STRAND 6..8 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 14..17 FT /evidence="ECO:0007829|PDB:1EYB" FT HELIX 36..38 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 40..47 FT /evidence="ECO:0007829|PDB:1EYB" FT HELIX 53..55 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 58..65 FT /evidence="ECO:0007829|PDB:1EYB" FT HELIX 85..87 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 95..97 FT /evidence="ECO:0007829|PDB:1EYB" FT TURN 105..107 FT /evidence="ECO:0007829|PDB:1EYB" FT TURN 112..115 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 116..123 FT /evidence="ECO:0007829|PDB:1EYB" FT HELIX 125..127 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 131..138 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 144..161 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 163..167 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 170..174 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 178..182 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 188..191 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 193..205 FT /evidence="ECO:0007829|PDB:1EYB" FT HELIX 214..216 FT /evidence="ECO:0007829|PDB:1EYB" FT HELIX 224..226 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 227..230 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 238..249 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 252..260 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 265..271 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 275..278 FT /evidence="ECO:0007829|PDB:1EYB" FT HELIX 279..281 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 288..291 FT /evidence="ECO:0007829|PDB:1EYB" FT HELIX 295..298 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 299..304 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 311..318 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 320..323 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 326..328 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 340..347 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 362..365 FT /evidence="ECO:0007829|PDB:1EYB" FT HELIX 375..383 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 389..392 FT /evidence="ECO:0007829|PDB:1EYB" FT STRAND 396..404 FT /evidence="ECO:0007829|PDB:1EYB" FT HELIX 410..415 FT /evidence="ECO:0007829|PDB:1EYB" SQ SEQUENCE 445 AA; 49964 MW; F99B51C134FFF965 CRC64; MAELKYISGF GNECSSEDPR CPGSLPEGQN NPQVCPYNLY AEQLSGSAFT CPRSTNKRSW LYRILPSVSH KPFESIDEGQ VTHNWDEVDP DPNQLRWKPF EIPKASQKKV DFVSGLHTLC GAGDIKSNNG LAIHIFLCNT SMENRCFYNS DGDFLIVPQK GNLLIYTEFG KMLVQPNEIC VIQRGMRFSI DVFEETRGYI LEVYGVHFEL PDLGPIGANG LANPRDFLIP IAWYEDRQVP GGYTVINKYQ GKLFAAKQDV SPFNVVAWHG NYTPYKYNLK NFMVINSVAF DHADPSIFTV LTAKSVRPGV AIADFVIFPP RWGVADKTFR PPYYHRNCMS EFMGLIRGHY EAKQGGFLPG GGSLHSTMTP HGPDADCFEK ASKVKLAPER IADGTMAFMF ESSLSLAVTK WGLKASRCLD ENYHKCWEPL KSHFTPNSRN PAEPN //