ID TY3H_HUMAN Reviewed; 528 AA. AC P07101; B7ZL70; B7ZL73; Q0PWM2; Q0PWM3; Q15585; Q15588; Q15589; Q2M3B4; DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot. DT 16-JUN-2009, sequence version 5. DT 27-MAR-2024, entry version 240. DE RecName: Full=Tyrosine 3-monooxygenase; DE EC=1.14.16.2 {ECO:0000269|PubMed:15287903, ECO:0000269|PubMed:1680128, ECO:0000269|PubMed:17391063, ECO:0000269|PubMed:24753243, ECO:0000269|PubMed:34922205, ECO:0000269|PubMed:8528210, ECO:0000269|Ref.18}; DE AltName: Full=Tyrosine 3-hydroxylase; DE Short=TH; GN Name=TH {ECO:0000312|HGNC:HGNC:11782}; Synonyms=TYH; 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] (ISOFORM 3). RX PubMed=2887169; DOI=10.1016/0006-291x(87)90742-x; RA Kaneda N., Kobayashi K., Ichinose H., Kishi F., Nakazawa A., Kurosawa Y., RA Fujita K., Nagatsu T.; RT "Isolation of a novel cDNA clone for human tyrosine hydroxylase: RT alternative RNA splicing produces four kinds of mRNA from a single gene."; RL Biochem. Biophys. Res. Commun. 146:971-975(1987). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND ALTERNATIVE SPLICING. RX PubMed=2882428; DOI=10.1038/326707a0; RA Grima B., Lamouroux A., Boni C., Julien J.-F., Javoy-Agid F., Mallet J.; RT "A single human gene encoding multiple tyrosine hydroxylases with different RT predicted functional characteristics."; RL Nature 326:707-711(1987). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=2888085; DOI=10.1093/nar/15.16.6733; RA Kobayashi K., Kaneda N., Ichinose H., Kishi F., Nakazawa A., Kurosawa Y., RA Fujita K., Nagatsu T.; RT "Isolation of a full-length cDNA clone encoding human tyrosine hydroxylase RT type 3."; RL Nucleic Acids Res. 15:6733-6733(1987). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING. RX PubMed=2902075; DOI=10.1093/oxfordjournals.jbchem.a122386; RA Kobayashi K., Kaneda N., Ichinose H., Kishi F., Nakazawa A., Kurosawa Y., RA Fujita K., Nagatsu T.; RT "Structure of the human tyrosine hydroxylase gene: alternative splicing RT from a single gene accounts for generation of four mRNA types."; RL J. Biochem. 103:907-912(1988). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 5 AND 6), ALTERNATIVE SPLICING, RP CATALYTIC ACTIVITY, AND PATHWAY. RX PubMed=17391063; DOI=10.1515/bc.2007.041; RA Roma J., Saus E., Cuadros M., Reventos J., Sanchez de Toledo J., RA Gallego S.; RT "Characterisation of novel splicing variants of the tyrosine hydroxylase C- RT terminal domain in human neuroblastic tumours."; RL Biol. Chem. 388:419-426(2007). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 4), AND VARIANT RP MET-112. 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 [9] RP PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2892893; DOI=10.1111/j.1471-4159.1988.tb03009.x; RA le Bourdelles B., Boularand S., Boni C., Horellou P., Dumas S., Grima B., RA Mallet J.; RT "Analysis of the 5' region of the human tyrosine hydroxylase gene: RT combinatorial patterns of exon splicing generate multiple regulated RT tyrosine hydroxylase isoforms."; RL J. Neurochem. 50:988-991(1988). RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-30. RX PubMed=2896667; DOI=10.1016/s0021-9258(18)68656-9; RA Ginns E.I., Rehavi M., Martin B.M., Weller M., O'Malley K.L., Lamarca M.E., RA McAllister C.G., Paul S.M.; RT "Expression of human tyrosine hydroxylase cDNA in invertebrate cells using RT a baculovirus vector."; RL J. Biol. Chem. 263:7406-7410(1988). RN [11] RP CATALYTIC ACTIVITY, FUNCTION, ACTIVITY REGULATION, AND PHOSPHORYLATION AT RP SER-19 AND SER-71. RX PubMed=1680128; DOI=10.1016/s0021-9258(19)47348-1; RA Le Bourdelles B., Horellou P., Le Caer J.P., Denefle P., Latta M., RA Haavik J., Guibert B., Mayaux J.F., Mallet J.; RT "Phosphorylation of human recombinant tyrosine hydroxylase isoforms 1 and RT 2: an additional phosphorylated residue in isoform 2, generated through RT alternative splicing."; RL J. Biol. Chem. 266:17124-17130(1991). RN [12] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND PHOSPHORYLATION AT RP SER-62 AND SER-71. RX PubMed=7901013; DOI=10.1111/j.1432-1033.1993.tb18297.x; RA Sutherland C., Alterio J., Campbell D.G., Le Bourdelles B., Mallet J., RA Haavik J., Cohen P.; RT "Phosphorylation and activation of human tyrosine hydroxylase in vitro by RT mitogen-activated protein (MAP) kinase and MAP-kinase-activated kinases 1 RT and 2."; RL Eur. J. Biochem. 217:715-722(1993). RN [13] RP ACTIVITY REGULATION, FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=15287903; DOI=10.1111/j.1471-4159.2004.02566.x; RA Sura G.R., Daubner S.C., Fitzpatrick P.F.; RT "Effects of phosphorylation by protein kinase A on binding of RT catecholamines to the human tyrosine hydroxylase isoforms."; RL J. Neurochem. 90:970-978(2004). RN [14] RP POSSIBLE INVOLVEMENT IN PARKINSON DISEASE. RX PubMed=20809526; DOI=10.1002/humu.21351; RA Bademci G., Edwards T.L., Torres A.L., Scott W.K., Zuchner S., Martin E.R., RA Vance J.M., Wang L.; RT "A rare novel deletion of the tyrosine hydroxylase gene in Parkinson RT disease."; RL Hum. Mutat. 31:E1767-E1771(2010). RN [15] RP INVOLVEMENT IN ARSEGS, AND VARIANT ARSEGS LYS-412. RX PubMed=7814018; DOI=10.1007/bf00225091; RA Luedecke B., Dworniczak B., Bartholome K.; RT "A point mutation in the tyrosine hydroxylase gene associated with Segawa's RT syndrome."; RL Hum. Genet. 95:123-125(1995). RN [16] RP VARIANT MET-112. RX PubMed=7789962; DOI=10.1007/bf00209496; RA Luedecke B., Bartholome K.; RT "Frequent sequence variant in the human tyrosine hydroxylase gene."; RL Hum. Genet. 95:716-716(1995). RN [17] RP FUNCTION, CATALYTIC ACTIVITY, AND CHARACTERIZATION OF VARIANT ARSEGS RP LYS-412. RX PubMed=8528210; DOI=10.1093/hmg/4.7.1209; RA Knappskog P.M., Flatmark T., Mallet J., Luedecke B., Bartholome K.; RT "Recessively inherited L-DOPA-responsive dystonia caused by a point RT mutation (Q381K) in the tyrosine hydroxylase gene."; RL Hum. Mol. Genet. 4:1209-1212(1995). RN [18] {ECO:0007744|PDB:2XSN} RP X-RAY CRYSTALLOGRAPHY (2.68 ANGSTROMS) OF 193-528, AND SUBUNIT. RA Muniz J.R.C., Cooper C.D.O., Yue W.W., Krysztofinska E., von Delft F., RA Knapp S., Gileadi O., Arrowsmith C.H., Edwards A.M., Weigelt J., RA Bountra C., Kavanagh K.L., Oppermann U.; RT "Crystal Structure of Human Tyrosine Hydroxylase Catalytic Domain."; RL Submitted (OCT-2010) to the PDB data bank. RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY, PHOSPHORYLATION AT SER-19 AND SER-62, RP INTERACTION WITH YWHAG, AND SUBUNIT. RX PubMed=24947669; DOI=10.1074/mcp.m113.035709; RA Kleppe R., Rosati S., Jorge-Finnigan A., Alvira S., Ghorbani S., Haavik J., RA Valpuesta J.M., Heck A.J., Martinez A.; RT "Phosphorylation dependence and stoichiometry of the complex formed by RT tyrosine hydroxylase and 14-3-3gamma."; RL Mol. Cell. Proteomics 13:2017-2030(2014). RN [20] RP PHOSPHORYLATION AT SER-62, SUBCELLULAR LOCATION, AND MUTAGENESIS OF SER-62. RX PubMed=28637871; DOI=10.1074/jbc.m116.762344; RA Jorge-Finnigan A., Kleppe R., Jung-Kc K., Ying M., Marie M., RA Rios-Mondragon I., Salvatore M.F., Saraste J., Martinez A.; RT "Phosphorylation at serine 31 targets tyrosine hydroxylase to vesicles for RT transport along microtubules."; RL J. Biol. Chem. 292:14092-14107(2017). RN [21] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, MUTAGENESIS OF SER-71 RP AND CYS-207, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=34922205; DOI=10.1016/j.bbrc.2021.12.024; RA Inukai S., Hara S., Ichinose H.; RT "Tyrosine hydroxylase activity is regulated through the modification of the RT 176th cysteine residue."; RL Biochem. Biophys. Res. Commun. 589:209-214(2022). RN [22] RP CHARACTERIZATION OF VARIANT ARSEGS PRO-236. RX PubMed=8817341; DOI=10.1093/hmg/5.7.1023; RA Luedecke B., Knappskog P.M., Clayton P.T., Surtees R.A.H., Clelland J.D., RA Heales S.J.R., Brand M.P., Bartholome K., Flatmark T.; RT "Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by RT a point mutation (L205P) in the tyrosine hydroxylase gene."; RL Hum. Mol. Genet. 5:1023-1028(1996). RN [23] RP VARIANT ARSEGS PRO-236, AND VARIANT MET-112. RX PubMed=9613851; RX DOI=10.1002/(sici)1096-8628(19980328)81:2<131::aid-ajmg2>3.3.co;2-x; RA Kunugi H., Kawada Y., Hattori M., Ueki A., Otsuka M., Nanko S.; RT "Association study of structural mutations of the tyrosine hydroxylase gene RT with schizophrenia and Parkinson's disease."; RL Am. J. Med. Genet. 81:131-133(1998). RN [24] RP VARIANT MET-499. RX PubMed=9754624; RX DOI=10.1002/(sici)1096-8628(19980907)81:5<388::aid-ajmg7>3.3.co;2-f; RA Ishiguro H., Arinami T., Saito T., Akazawa S., Enomoto M., Mitushio H., RA Fujishiro H., Tada K., Akimoto Y., Mifune H., Shiozuka S., Hamaguchi H., RA Toru M., Shibuya H.; RT "Systematic search for variations in the tyrosine hydroxylase gene and RT their associations with schizophrenia, affective disorders, and RT alcoholism."; RL Am. J. Med. Genet. 81:388-396(1998). RN [25] RP VARIANT ARSEGS HIS-233. RX PubMed=9703425; DOI=10.1007/s004390050756; RA van den Heuvel L.P.W.J., Luiten B., Smeitink J.A.M., RA de Rijk-van Andel J.F., Hyland K., Steenbergen-Spanjers G.C.H., RA Janssen R.J.T., Wevers R.A.; RT "A common point mutation in the tyrosine hydroxylase gene in autosomal RT recessive L-DOPA-responsive dystonia in the Dutch population."; RL Hum. Genet. 102:644-646(1998). RN [26] RP VARIANT ARSEGS PHE-359. RX PubMed=10585338; RA Braeutigam C., Steenbergen-Spanjers G.C., Hoffmann G.F., Dionisi-Vici C., RA van den Heuvel L.P., Smeitink J.A., Wevers R.A.; RT "Biochemical and molecular genetic characteristics of the severe form of RT tyrosine hydroxylase deficiency."; RL Clin. Chem. 45:2073-2078(1999). RN [27] RP VARIANT MET-112. RX PubMed=10391209; DOI=10.1038/10290; RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RT "Characterization of single-nucleotide polymorphisms in coding regions of RT human genes."; RL Nat. Genet. 22:231-238(1999). RN [28] RP ERRATUM OF PUBMED:10391209. RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RL Nat. Genet. 23:373-373(1999). RN [29] RP VARIANTS ARSEGS PRO-276; MET-314; HIS-337 AND MET-494. RX PubMed=11246459; DOI=10.1017/s0003480000007922; RA Swaans R.J.M., Rondot P., Renier W.O., Van Den Heuvel L.P.W.J., RA Steenbergen-Spanjers G.C.H., Wevers R.A.; RT "Four novel mutations in the tyrosine hydroxylase gene in patients with RT infantile parkinsonism."; RL Ann. Hum. Genet. 64:25-31(2000). RN [30] RP VARIANT ARSEGS SER-309. RX PubMed=11196107; DOI=10.1023/a:1026760602577; RA De Lonlay P., Nassogne M.C., van Gennip A.H., van Cruchten A.C., RA Billatte de Villemeur T., Cretz M., Stoll C., Launay J.M., RA Steenberger-Spante G.C., van den Heuvel L.P., Wevers R.A., Saudubray J.M., RA Abeling N.G.; RT "Tyrosine hydroxylase deficiency unresponsive to L-dopa treatment with RT unusual clinical and biochemical presentation."; RL J. Inherit. Metab. Dis. 23:819-825(2000). RN [31] RP VARIANTS ARSEGS VAL-376 AND GLY-498. RX PubMed=15505183; DOI=10.1212/01.wnl.0000142083.47927.0a; RA Schiller A., Wevers R.A., Steenbergen G.C., Blau N., Jung H.H.; RT "Long-term course of L-dopa-responsive dystonia caused by tyrosine RT hydroxylase deficiency."; RL Neurology 63:1524-1526(2004). RN [32] RP VARIANTS ARSEGS TYR-246 AND GLY-498. RX PubMed=15747353; DOI=10.1002/mds.20416; RA Diepold K., Schuetz B., Rostasy K., Wilken B., Hougaard P., Guettler F., RA Romstad A., Birk Moeller L.; RT "Levodopa-responsive infantile parkinsonism due to a novel mutation in the RT tyrosine hydroxylase gene and exacerbation by viral infections."; RL Mov. Disord. 20:764-767(2005). RN [33] RP VARIANTS ARSEGS TRP-328 AND MET-399. RX PubMed=16049992; DOI=10.1002/pd.1193; RA Moeller L.B., Romstad A., Paulsen M., Hougaard P., Ormazabal A., Pineda M., RA Blau N., Guettler F., Artuch R.; RT "Pre- and postnatal diagnosis of tyrosine hydroxylase deficiency."; RL Prenat. Diagn. 25:671-675(2005). RN [34] RP VARIANTS ARSEGS MET-387 AND LEU-492. RX PubMed=17696123; DOI=10.1002/ana.21199; RA Verbeek M.M., Steenbergen-Spanjers G.C., Willemsen M.A., Hol F.A., RA Smeitink J., Seeger J., Grattan-Smith P., Ryan M.M., Hoffmann G.F., RA Donati M.A., Blau N., Wevers R.A.; RT "Mutations in the cyclic adenosine monophosphate response element of the RT tyrosine hydroxylase gene."; RL Ann. Neurol. 62:422-426(2007). RN [35] RP VARIANTS ARSEGS ARG-414 AND GLN-510. RX PubMed=18058633; DOI=10.1055/s-2007-991151; RA Giovanniello T., Leuzzi V., Carducci C., Carducci C., Sabato M.L., RA Artiola C., Santagata S., Pozzessere S., Antonozzi I.; RT "Tyrosine hydroxylase deficiency presenting with a biphasic clinical RT course."; RL Neuropediatrics 38:213-215(2007). RN [36] RP VARIANTS ARSEGS HIS-233 AND SER-247. RX PubMed=18554280; DOI=10.1111/j.1399-0004.2008.01039.x; RA Wu Z.Y., Lin Y., Chen W.J., Zhao G.X., Xie H., Murong S.X., Wang N.; RT "Molecular analyses of GCH-1, TH and parkin genes in Chinese dopa- RT responsive dystonia families."; RL Clin. Genet. 74:513-521(2008). RN [37] RP VARIANTS ARSEGS ALA-301; PRO-319; LEU-375; ARG-414 AND GLY-467. RX PubMed=19491146; DOI=10.1093/brain/awp084; RA Clot F., Grabli D., Cazeneuve C., Roze E., Castelnau P., Chabrol B., RA Landrieu P., Nguyen K., Ponsot G., Abada M., Doummar D., Damier P., Gil R., RA Thobois S., Ward A.J., Hutchinson M., Toutain A., Picard F., Camuzat A., RA Fedirko E., San C., Bouteiller D., LeGuern E., Durr A., Vidailhet M., RA Brice A.; RT "Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients RT with Dopa-responsive dystonia."; RL Brain 132:1753-1763(2009). RN [38] RP VARIANTS ARSEGS TYR-207; GLY-227; THR-241; GLY-259 AND THR-394. RX PubMed=20430833; DOI=10.1093/brain/awq087; RA Willemsen M.A., Verbeek M.M., Kamsteeg E.J., de Rijk-van Andel J.F., RA Aeby A., Blau N., Burlina A., Donati M.A., Geurtz B., Grattan-Smith P.J., RA Haeussler M., Hoffmann G.F., Jung H., de Klerk J.B., van der Knaap M.S., RA Kok F., Leuzzi V., de Lonlay P., Megarbane A., Monaghan H., Renier W.O., RA Rondot P., Ryan M.M., Seeger J., Smeitink J.A., Steenbergen-Spanjers G.C., RA Wassmer E., Weschke B., Wijburg F.A., Wilcken B., Zafeiriou D.I., RA Wevers R.A.; RT "Tyrosine hydroxylase deficiency: a treatable disorder of brain RT catecholamine biosynthesis."; RL Brain 133:1810-1822(2010). RN [39] RP VARIANTS ARSEGS ARG-294; SER-315; VAL-385; THR-394 AND ARG-408. RX PubMed=20056467; DOI=10.1016/j.ymgme.2009.12.011; RA Mak C.M., Lam C.W., Siu T.S., Chan K.Y., Siu W.K., Yeung W.L., Hui J., RA Wong V.C., Low L.C., Ko C.H., Fung C.W., Chen S.P., Yuen Y.P., Lee H.C., RA Yau E., Chan B., Tong S.F., Tam S., Chan Y.W.; RT "Biochemical and molecular characterization of tyrosine hydroxylase RT deficiency in Hong Kong Chinese."; RL Mol. Genet. Metab. 99:431-433(2010). RN [40] RP VARIANTS ARSEGS PRO-441 AND GLY-498. RX PubMed=23939262; DOI=10.3233/jpd-2011-11006; RA Haugarvoll K., Bindoff L.A.; RT "A novel compound heterozygous tyrosine hydroxylase mutation (p.R441P) with RT complex phenotype."; RL J. Parkinson's Dis. 1:119-122(2011). RN [41] RP VARIANTS ARSEGS LEU-251; PHE-279 AND GLN-296, AND VARIANT MET-112. RX PubMed=21940685; DOI=10.1177/0883073811420717; RA Giovanniello T., Claps D., Carducci C., Carducci C., Blau N., Vigevano F., RA Antonozzi I., Leuzzi V.; RT "A new tyrosine hydroxylase genotype associated with early-onset severe RT encephalopathy."; RL J. Child Neurol. 27:523-525(2012). RN [42] RP VARIANT ARSEGS ARG-428. RX PubMed=22815559; DOI=10.1212/wnl.0b013e318261714a; RA Stamelou M., Mencacci N.E., Cordivari C., Batla A., Wood N.W., Houlden H., RA Hardy J., Bhatia K.P.; RT "Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency."; RL Neurology 79:435-441(2012). RN [43] RP VARIANTS ARSEGS HIS-233; SER-315 AND THR-382. RX PubMed=22264700; DOI=10.1016/j.pediatrneurol.2011.11.012; RA Chi C.S., Lee H.F., Tsai C.R.; RT "Tyrosine hydroxylase deficiency in Taiwanese infants."; RL Pediatr. Neurol. 46:77-82(2012). RN [44] RP VARIANTS CYS-19 AND ARG-428. RX PubMed=23762320; DOI=10.1371/journal.pone.0065215; RA Cai C., Shi W., Zeng Z., Zhang M., Ling C., Chen L., Cai C., Zhang B., RA Li W.D.; RT "GTP cyclohydrolase I and tyrosine hydroxylase gene mutations in familial RT and sporadic dopa-responsive dystonia patients."; RL PLoS ONE 8:E65215-E65215(2013). RN [45] RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND RP CHARACTERIZATION OF VARIANTS ARSEGS TYR-207; GLY-227; HIS-233; PRO-236; RP THR-241; TYR-246; SER-247; GLY-259; PRO-276; ALA-301; SER-309; MET-314; RP PRO-319; TRP-328; HIS-337; PHE-359; LEU-375; VAL-376; MET-387; THR-394; RP MET-399; LYS-412; ARG-414; PRO-441; GLY-467; LEU-492; MET-494; GLY-498 AND RP GLN-510. RX PubMed=24753243; DOI=10.1002/humu.22565; RA Fossbakk A., Kleppe R., Knappskog P.M., Martinez A., Haavik J.; RT "Functional studies of tyrosine hydroxylase missense variants reveal RT distinct patterns of molecular defects in Dopa-responsive dystonia."; RL Hum. Mutat. 35:880-890(2014). CC -!- FUNCTION: Catalyzes the conversion of L-tyrosine to L- CC dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the CC biosynthesis of cathecolamines, dopamine, noradrenaline, and CC adrenaline. Uses tetrahydrobiopterin and molecular oxygen to convert CC tyrosine to L-Dopa (PubMed:17391063, PubMed:1680128, PubMed:15287903, CC PubMed:8528210, Ref.18, PubMed:34922205, PubMed:24753243). In addition CC to tyrosine, is able to catalyze the hydroxylation of phenylalanine and CC tryptophan with lower specificity (By similarity). Positively regulates CC the regression of retinal hyaloid vessels during postnatal development CC (By similarity). {ECO:0000250|UniProtKB:P04177, CC ECO:0000250|UniProtKB:P24529, ECO:0000269|PubMed:15287903, CC ECO:0000269|PubMed:1680128, ECO:0000269|PubMed:17391063, CC ECO:0000269|PubMed:24753243, ECO:0000269|PubMed:34922205, CC ECO:0000269|PubMed:8528210, ECO:0000269|Ref.18}. CC -!- FUNCTION: [Isoform 5]: Lacks catalytic activity. CC {ECO:0000269|PubMed:17391063}. CC -!- FUNCTION: [Isoform 6]: Lacks catalytic activity. CC {ECO:0000269|PubMed:17391063}. CC -!- CATALYTIC ACTIVITY: CC Reaction=(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + L-tyrosine + O2 = CC (4aS,6R)-4a-hydroxy-L-erythro-5,6,7,8-tetrahydrobiopterin + L-dopa; CC Xref=Rhea:RHEA:18201, ChEBI:CHEBI:15379, ChEBI:CHEBI:15642, CC ChEBI:CHEBI:57504, ChEBI:CHEBI:58315, ChEBI:CHEBI:59560; CC EC=1.14.16.2; Evidence={ECO:0000269|PubMed:15287903, CC ECO:0000269|PubMed:1680128, ECO:0000269|PubMed:17391063, CC ECO:0000269|PubMed:24753243, ECO:0000269|PubMed:34922205, CC ECO:0000269|PubMed:8528210, ECO:0000269|Ref.18}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:18202; CC Evidence={ECO:0000305|PubMed:17391063}; CC -!- COFACTOR: CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033; CC Evidence={ECO:0000250|UniProtKB:P04177}; CC -!- ACTIVITY REGULATION: Inhibited in feedback fashion by the catecholamine CC neurotransmitters, especially by dopamine in competition with CC tetrahydrobiopterin (PubMed:15287903). Phosphorylation of several CC Ser/Thr residues in the N-terminus regulates the catalytic activity CC (PubMed:1680128, PubMed:7901013). Ser-62 and Ser-71 are readily CC phosphorylated to activate the catalytic activity (PubMed:1680128, CC PubMed:7901013). A Cysteine modification induced by N-ethylmaleimide CC (NEM), inhibits tyrosine 3-monooxygenase activity through the CC modification of the Cys-207 (PubMed:34922205). CC {ECO:0000269|PubMed:15287903, ECO:0000269|PubMed:1680128, CC ECO:0000269|PubMed:34922205, ECO:0000269|PubMed:7901013}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=39 uM for 6R-tetrahydrobiopterin {ECO:0000269|PubMed:24753243}; CC KM=5.1 uM for L-tyrosine {ECO:0000269|PubMed:24753243}; CC KM=35 uM for L-tyrosine (in presence of N-ethylmaleimide) CC {ECO:0000269|PubMed:34922205}; CC KM=15 uM for L-tyrosine {ECO:0000269|PubMed:34922205}; CC KM=57 uM for 6R-tetrahydrobiopterin {ECO:0000269|PubMed:34922205}; CC KM=32 uM for 6R-tetrahydrobiopterin (in presence of N-ethylmaleimide) CC {ECO:0000269|PubMed:34922205}; CC Vmax=591 nmol/min/mg enzyme with 6R-tetrahydrobiopterin as substrate CC {ECO:0000269|PubMed:24753243}; CC Vmax=2460 nmol/min/mg enzyme with L-tyrosine as substrate CC {ECO:0000269|PubMed:24753243}; CC Vmax=35 nmol/min/mg enzyme with L-tyrosine as substrate (in presence CC of N-ethylmaleimide) {ECO:0000269|PubMed:34922205}; CC Vmax=141 nmol/min/mg enzyme with L-tyrosine as substrate CC {ECO:0000269|PubMed:34922205}; CC Vmax=26 nmol/min/mg enzyme with 6R-tetrahydrobiopterin as substrate CC (in presence of N-ethylmaleimide) {ECO:0000269|PubMed:34922205}; CC Vmax=138 nmol/min/mg enzyme with 6R-tetrahydrobiopterin as substrate CC {ECO:0000269|PubMed:34922205}; CC -!- PATHWAY: Catecholamine biosynthesis; dopamine biosynthesis; dopamine CC from L-tyrosine: step 1/2. {ECO:0000269|PubMed:17391063}. CC -!- SUBUNIT: Homotetramer (Ref.18, PubMed:24947669). Interacts (when CC phosphorylated at Ser-19) with YWHAG; one YWHAG dimer bounds to one TH CC tetramer, this interaction may influence the phosphorylation and CC dephosphorylation of other sites (PubMed:24947669). CC {ECO:0000269|PubMed:24947669, ECO:0000269|Ref.18}. CC -!- INTERACTION: CC P07101-3; P29762: CRABP1; NbExp=3; IntAct=EBI-12001016, EBI-725950; CC P07101-3; P61978-2: HNRNPK; NbExp=3; IntAct=EBI-12001016, EBI-7060731; CC P07101-3; Q99750: MDFI; NbExp=3; IntAct=EBI-12001016, EBI-724076; CC P07101-3; P08651-5: NFIC; NbExp=3; IntAct=EBI-12001016, EBI-18939222; CC P07101-3; O75928-2: PIAS2; NbExp=3; IntAct=EBI-12001016, EBI-348567; CC P07101-3; Q9UHX1-2: PUF60; NbExp=3; IntAct=EBI-12001016, EBI-11529177; CC P07101-3; P0DJD3-2: RBMY1A1; NbExp=3; IntAct=EBI-12001016, EBI-11994018; CC P07101-3; P07101-3: TH; NbExp=5; IntAct=EBI-12001016, EBI-12001016; CC P07101-3; Q9UJ04: TSPYL4; NbExp=3; IntAct=EBI-12001016, EBI-308511; CC P07101-3; C9J7I0: UMAD1; NbExp=3; IntAct=EBI-12001016, EBI-10989060; CC P07101-3; Q5MCW4: ZNF569; NbExp=3; IntAct=EBI-12001016, EBI-4395687; CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region CC {ECO:0000250|UniProtKB:P24529}. Nucleus {ECO:0000250|UniProtKB:P04177}. CC Cell projection, axon {ECO:0000250|UniProtKB:P24529}. Cytoplasm CC {ECO:0000250|UniProtKB:P04177}. Cytoplasmic vesicle, secretory vesicle, CC synaptic vesicle {ECO:0000250|UniProtKB:P04177}. Note=When CC phosphorylated at Ser-19 shows a nuclear distribution and when CC phosphorylated at Ser-31 as well at Ser-40 shows a cytosolic CC distribution (By similarity). Expressed in dopaminergic axons and axon CC terminals. {ECO:0000250|UniProtKB:P04177}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Comment=TH transcripts lacking exons 8 and 9 present concomitant CC splicing in exons 1b and 2.; CC Name=3; Synonyms=TH type 4; CC IsoId=P07101-1; Sequence=Displayed; CC Name=1; Synonyms=TH type 3; CC IsoId=P07101-2; Sequence=VSP_000543; CC Name=2; Synonyms=HTH-1 {ECO:0000303|PubMed:2882428}, hTH-Delta1b,2, TH CC type 1; CC IsoId=P07101-3; Sequence=VSP_000544; CC Name=4; Synonyms=hTH-Delta2, TH type 2; CC IsoId=P07101-4; Sequence=VSP_000541; CC Name=5; Synonyms=hTH-Delta2,8,9 {ECO:0000303|PubMed:17391063}; CC IsoId=P07101-5; Sequence=VSP_000541, VSP_054338; CC Name=6; Synonyms=hTH-Delta1b,2,8,9 {ECO:0000303|PubMed:17391063}; CC IsoId=P07101-6; Sequence=VSP_000544, VSP_054338; CC -!- TISSUE SPECIFICITY: Mainly expressed in the brain and adrenal glands. CC -!- PTM: Phosphorylated on Ser-19, Ser-62 and Ser-71 by several protein CC kinases with different site specificities. Phosphorylation at Ser-62 CC and Ser-71 leads to an increase of TH activity (PubMed:7901013). CC Phosphorylation at Ser-71 activates the enzyme and also counteracts the CC feedback inhibition of TH by catecholamines (PubMed:15287903). CC Phosphorylation of Ser-19 and Ser-62 triggers the proteasomal CC degradation of TH through the ubiquitin-proteasome pathway (By CC similarity). Phosphorylation at Ser-62 facilitates transport of TH from CC the soma to the nerve terminals via the microtubule network CC (PubMed:28637871). Phosphorylation at Ser-19 induces the high-affinity CC binding to the 14-3-3 protein YWHAG; this interaction may influence the CC phosphorylation and dephosphorylation of other sites (PubMed:24947669). CC Ser-19 increases the phosphorylation at Ser-71 in a hierarchical CC manner, leading to increased activity (By similarity). CC {ECO:0000250|UniProtKB:P04177, ECO:0000269|PubMed:15287903, CC ECO:0000269|PubMed:24947669, ECO:0000269|PubMed:28637871, CC ECO:0000269|PubMed:7901013}. CC -!- DISEASE: Segawa syndrome autosomal recessive (ARSEGS) [MIM:605407]: A CC form of DOPA-responsive dystonia presenting in infancy or early CC childhood. Dystonia is defined by the presence of sustained involuntary CC muscle contractions, often leading to abnormal postures. Some cases CC present with parkinsonian symptoms in infancy. Unlike all other forms CC of dystonia, it is an eminently treatable condition, due to a favorable CC response to L-DOPA. {ECO:0000269|PubMed:10585338, CC ECO:0000269|PubMed:11196107, ECO:0000269|PubMed:11246459, CC ECO:0000269|PubMed:15505183, ECO:0000269|PubMed:15747353, CC ECO:0000269|PubMed:16049992, ECO:0000269|PubMed:17696123, CC ECO:0000269|PubMed:18058633, ECO:0000269|PubMed:18554280, CC ECO:0000269|PubMed:19491146, ECO:0000269|PubMed:20056467, CC ECO:0000269|PubMed:20430833, ECO:0000269|PubMed:21940685, CC ECO:0000269|PubMed:22264700, ECO:0000269|PubMed:22815559, CC ECO:0000269|PubMed:23762320, ECO:0000269|PubMed:23939262, CC ECO:0000269|PubMed:24753243, ECO:0000269|PubMed:7814018, CC ECO:0000269|PubMed:8528210, ECO:0000269|PubMed:8817341, CC ECO:0000269|PubMed:9613851, ECO:0000269|PubMed:9703425}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Note=May play a role in the pathogenesis of Parkinson disease CC (PD). A genome-wide copy number variation analysis has identified a 34 CC kilobase deletion over the TH gene in a PD patient but not in any CC controls. {ECO:0000269|PubMed:20809526}. CC -!- SIMILARITY: Belongs to the biopterin-dependent aromatic amino acid CC hydroxylase family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA61173.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Tyrosine hydroxylase entry; CC URL="https://en.wikipedia.org/wiki/Tyrosine_hydroxylase"; 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; M17589; AAA61179.1; -; mRNA. DR EMBL; X05290; CAA28908.1; -; mRNA. DR EMBL; Y00414; CAA68472.1; -; mRNA. DR EMBL; DQ677336; ABG73364.1; -; mRNA. DR EMBL; DQ677337; ABG73365.1; -; mRNA. DR EMBL; AC132217; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; M24791; AAA61173.1; ALT_SEQ; Genomic_DNA. DR EMBL; M24787; AAA61173.1; JOINED; Genomic_DNA. DR EMBL; M24789; AAA61173.1; JOINED; Genomic_DNA. DR EMBL; CH471158; EAX02493.1; -; Genomic_DNA. DR EMBL; BC104967; AAI04968.1; -; mRNA. DR EMBL; BC143611; AAI43612.1; -; mRNA. DR EMBL; BC143614; AAI43615.1; -; mRNA. DR EMBL; M24791; AAA61170.1; -; Genomic_DNA. DR EMBL; M24787; AAA61170.1; JOINED; Genomic_DNA. DR EMBL; M20911; AAA61167.1; -; mRNA. DR CCDS; CCDS31338.1; -. [P07101-2] DR CCDS; CCDS7730.1; -. [P07101-3] DR CCDS; CCDS7731.1; -. [P07101-1] DR PIR; A30002; WHHUY4. DR RefSeq; NP_000351.2; NM_000360.3. [P07101-3] DR RefSeq; NP_954986.2; NM_199292.2. [P07101-1] DR RefSeq; NP_954987.2; NM_199293.2. [P07101-2] DR RefSeq; XP_011518637.1; XM_011520335.2. [P07101-4] DR PDB; 2XSN; X-ray; 2.68 A; A/B/C/D=193-528. DR PDB; 4J6S; X-ray; 3.08 A; E/F/G/H=1-74. DR PDB; 6ZN2; EM; 4.30 A; A/C/E/G=194-528. DR PDB; 6ZVP; EM; 4.00 A; A/B/C/D=71-528. DR PDB; 6ZZU; EM; 3.50 A; A/B/C/D=194-528. DR PDB; 7A2G; EM; 4.10 A; A/B/C/D=109-528. DR PDB; 7PIM; EM; 4.60 A; A/B/D/F=194-528. DR PDBsum; 2XSN; -. DR PDBsum; 4J6S; -. DR PDBsum; 6ZN2; -. DR PDBsum; 6ZVP; -. DR PDBsum; 6ZZU; -. DR PDBsum; 7A2G; -. DR PDBsum; 7PIM; -. DR AlphaFoldDB; P07101; -. DR EMDB; EMD-11309; -. DR EMDB; EMD-11467; -. DR EMDB; EMD-11587; -. DR EMDB; EMD-11624; -. DR EMDB; EMD-13442; -. DR SASBDB; P07101; -. DR SMR; P07101; -. DR BioGRID; 112912; 39. DR ELM; P07101; -. DR IntAct; P07101; 23. DR MINT; P07101; -. DR STRING; 9606.ENSP00000370571; -. DR BindingDB; P07101; -. DR ChEMBL; CHEMBL1969; -. DR DrugBank; DB03552; 3-Tyrosine. DR DrugBank; DB04400; L-erythro-7,8-dihydrobiopterin. DR DrugBank; DB00765; Metyrosine. DR DrugBank; DB00120; Phenylalanine. DR DrugBank; DB00360; Sapropterin. DR DrugBank; DB00135; Tyrosine. DR DrugCentral; P07101; -. DR iPTMnet; P07101; -. DR PhosphoSitePlus; P07101; -. DR BioMuta; TH; -. DR DMDM; 239938945; -. DR EPD; P07101; -. DR jPOST; P07101; -. DR MassIVE; P07101; -. DR PaxDb; 9606-ENSP00000370571; -. DR PeptideAtlas; P07101; -. DR ProteomicsDB; 51950; -. [P07101-1] DR ProteomicsDB; 51951; -. [P07101-2] DR ProteomicsDB; 51952; -. [P07101-3] DR ProteomicsDB; 51953; -. [P07101-4] DR ProteomicsDB; 58784; -. DR Antibodypedia; 3748; 1915 antibodies from 51 providers. DR DNASU; 7054; -. DR Ensembl; ENST00000333684.9; ENSP00000328814.6; ENSG00000180176.15. [P07101-6] DR Ensembl; ENST00000352909.8; ENSP00000325951.4; ENSG00000180176.15. [P07101-3] DR Ensembl; ENST00000381175.5; ENSP00000370567.1; ENSG00000180176.15. [P07101-2] DR Ensembl; ENST00000381178.5; ENSP00000370571.1; ENSG00000180176.15. [P07101-1] DR GeneID; 7054; -. DR KEGG; hsa:7054; -. DR MANE-Select; ENST00000352909.8; ENSP00000325951.4; NM_000360.4; NP_000351.2. [P07101-3] DR UCSC; uc001lvp.3; human. [P07101-1] DR AGR; HGNC:11782; -. DR CTD; 7054; -. DR DisGeNET; 7054; -. DR GeneCards; TH; -. DR GeneReviews; TH; -. DR HGNC; HGNC:11782; TH. DR HPA; ENSG00000180176; Group enriched (adrenal gland, brain). DR MalaCards; TH; -. DR MIM; 191290; gene. DR MIM; 605407; phenotype. DR neXtProt; NX_P07101; -. DR OpenTargets; ENSG00000180176; -. DR Orphanet; 101150; Autosomal recessive dopa-responsive dystonia. DR PharmGKB; PA351; -. DR VEuPathDB; HostDB:ENSG00000180176; -. DR eggNOG; KOG3820; Eukaryota. DR GeneTree; ENSGT00950000182885; -. DR HOGENOM; CLU_023198_3_0_1; -. DR InParanoid; P07101; -. DR OMA; VRYNPHT; -. DR OrthoDB; 275463at2759; -. DR PhylomeDB; P07101; -. DR TreeFam; TF313327; -. DR BRENDA; 1.14.16.2; 2681. DR PathwayCommons; P07101; -. DR Reactome; R-HSA-209905; Catecholamine biosynthesis. DR SABIO-RK; P07101; -. DR SignaLink; P07101; -. DR SIGNOR; P07101; -. DR UniPathway; UPA00747; UER00733. DR BioGRID-ORCS; 7054; 9 hits in 1159 CRISPR screens. DR GeneWiki; Tyrosine_hydroxylase; -. DR GenomeRNAi; 7054; -. DR Pharos; P07101; Tclin. DR PRO; PR:P07101; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; P07101; Protein. DR Bgee; ENSG00000180176; Expressed in substantia nigra pars reticulata and 105 other cell types or tissues. DR ExpressionAtlas; P07101; baseline and differential. DR GO; GO:0030424; C:axon; IBA:GO_Central. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:BHF-UCL. DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0030425; C:dendrite; IEA:Ensembl. DR GO; GO:0033162; C:melanosome membrane; IDA:BHF-UCL. DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl. DR GO; GO:0043005; C:neuron projection; IDA:BHF-UCL. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0043204; C:perikaryon; ISS:BHF-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB. DR GO; GO:0005790; C:smooth endoplasmic reticulum; IDA:BHF-UCL. DR GO; GO:0008021; C:synaptic vesicle; IEA:UniProtKB-SubCell. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0016597; F:amino acid binding; IEA:Ensembl. DR GO; GO:0035240; F:dopamine binding; IEA:Ensembl. DR GO; GO:0019899; F:enzyme binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0008199; F:ferric iron binding; IEA:Ensembl. DR GO; GO:0008198; F:ferrous iron binding; IEA:Ensembl. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0019825; F:oxygen binding; IEA:Ensembl. DR GO; GO:0019904; F:protein domain specific binding; IEA:Ensembl. DR GO; GO:0034617; F:tetrahydrobiopterin binding; IEA:Ensembl. DR GO; GO:0004511; F:tyrosine 3-monooxygenase activity; IDA:UniProtKB. DR GO; GO:0015842; P:aminergic neurotransmitter loading into synaptic vesicle; IEA:Ensembl. DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:ProtInc. DR GO; GO:0009887; P:animal organ morphogenesis; ISS:BHF-UCL. DR GO; GO:0071312; P:cellular response to alkaloid; IEA:Ensembl. DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl. DR GO; GO:0071287; P:cellular response to manganese ion; IEA:Ensembl. DR GO; GO:0071316; P:cellular response to nicotine; IEA:Ensembl. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl. DR GO; GO:0042745; P:circadian sleep/wake cycle; IEA:Ensembl. DR GO; GO:0042416; P:dopamine biosynthetic process; IDA:BHF-UCL. DR GO; GO:0006585; P:dopamine biosynthetic process from tyrosine; IBA:GO_Central. DR GO; GO:0042755; P:eating behavior; IEA:Ensembl. DR GO; GO:0048596; P:embryonic camera-type eye morphogenesis; ISS:BHF-UCL. DR GO; GO:0042418; P:epinephrine biosynthetic process; IDA:BHF-UCL. DR GO; GO:0042462; P:eye photoreceptor cell development; ISS:BHF-UCL. DR GO; GO:0006631; P:fatty acid metabolic process; IEA:Ensembl. DR GO; GO:0016137; P:glycoside metabolic process; IEA:Ensembl. DR GO; GO:0007507; P:heart development; ISS:BHF-UCL. DR GO; GO:0003007; P:heart morphogenesis; NAS:BHF-UCL. DR GO; GO:1990384; P:hyaloid vascular plexus regression; ISS:UniProtKB. DR GO; GO:0033076; P:isoquinoline alkaloid metabolic process; IEA:Ensembl. DR GO; GO:0007612; P:learning; ISS:BHF-UCL. DR GO; GO:0007626; P:locomotory behavior; ISS:BHF-UCL. DR GO; GO:0007617; P:mating behavior; IEA:Ensembl. DR GO; GO:0007613; P:memory; ISS:BHF-UCL. DR GO; GO:0042421; P:norepinephrine biosynthetic process; IDA:BHF-UCL. DR GO; GO:0018963; P:phthalate metabolic process; IEA:Ensembl. DR GO; GO:0052314; P:phytoalexin metabolic process; IEA:Ensembl. DR GO; GO:0043473; P:pigmentation; TAS:BHF-UCL. DR GO; GO:0008016; P:regulation of heart contraction; ISS:BHF-UCL. DR GO; GO:0014823; P:response to activity; IEA:Ensembl. DR GO; GO:0001975; P:response to amphetamine; IEA:Ensembl. DR GO; GO:0051412; P:response to corticosterone; IEA:Ensembl. DR GO; GO:0051602; P:response to electrical stimulus; IEA:Ensembl. DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl. DR GO; GO:0045471; P:response to ethanol; IDA:BHF-UCL. DR GO; GO:0045472; P:response to ether; IEA:Ensembl. DR GO; GO:0009635; P:response to herbicide; IEA:Ensembl. DR GO; GO:0001666; P:response to hypoxia; IDA:BHF-UCL. DR GO; GO:0035902; P:response to immobilization stress; IEA:Ensembl. DR GO; GO:0035900; P:response to isolation stress; IEA:Ensembl. DR GO; GO:0009416; P:response to light stimulus; IEA:Ensembl. DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl. DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl. DR GO; GO:0043434; P:response to peptide hormone; IEA:Ensembl. DR GO; GO:0046684; P:response to pyrethroid; IEA:Ensembl. DR GO; GO:0009651; P:response to salt stress; IEA:Ensembl. DR GO; GO:0010043; P:response to zinc ion; IEA:Ensembl. DR GO; GO:0035176; P:social behavior; IEA:Ensembl. DR GO; GO:0006665; P:sphingolipid metabolic process; IEA:Ensembl. DR GO; GO:0001963; P:synaptic transmission, dopaminergic; ISS:BHF-UCL. DR GO; GO:0042214; P:terpene metabolic process; IEA:Ensembl. DR GO; GO:0007601; P:visual perception; ISS:BHF-UCL. DR CDD; cd04930; ACT_TH; 1. DR CDD; cd03345; eu_TyrOH; 1. DR Gene3D; 3.30.70.260; -; 1. DR Gene3D; 1.10.800.10; Aromatic amino acid hydroxylase; 1. DR InterPro; IPR045865; ACT-like_dom_sf. DR InterPro; IPR001273; ArAA_hydroxylase. DR InterPro; IPR018301; ArAA_hydroxylase_Fe/CU_BS. DR InterPro; IPR036951; ArAA_hydroxylase_sf. DR InterPro; IPR036329; Aro-AA_hydroxylase_C_sf. DR InterPro; IPR019774; Aromatic-AA_hydroxylase_C. DR InterPro; IPR041903; Eu_TyrOH_cat. DR InterPro; IPR049321; TH_ACT. DR InterPro; IPR005962; Tyr_3_mOase. DR InterPro; IPR019773; Tyrosine_3-monooxygenase-like. DR InterPro; IPR021164; Tyrosine_hydroxylase_CS. DR NCBIfam; TIGR01269; Tyr_3_monoox; 1. DR PANTHER; PTHR11473; AROMATIC AMINO ACID HYDROXYLASE; 1. DR PANTHER; PTHR11473:SF18; TYROSINE 3-MONOOXYGENASE; 1. DR Pfam; PF00351; Biopterin_H; 1. DR Pfam; PF21417; TH_ACT; 1. DR Pfam; PF12549; TOH_N; 2. DR PIRSF; PIRSF000336; TH; 1. DR PRINTS; PR00372; FYWHYDRXLASE. DR SUPFAM; SSF55021; ACT-like; 1. DR SUPFAM; SSF56534; Aromatic aminoacid monoxygenases, catalytic and oligomerization domains; 1. DR PROSITE; PS00367; BH4_AAA_HYDROXYL_1; 1. DR PROSITE; PS51410; BH4_AAA_HYDROXYL_2; 1. DR Genevisible; P07101; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Catecholamine biosynthesis; KW Cell projection; Cytoplasm; Cytoplasmic vesicle; Disease variant; Dystonia; KW Iron; Metal-binding; Monooxygenase; Neurotransmitter biosynthesis; Nucleus; KW Oxidoreductase; Parkinson disease; Parkinsonism; Phosphoprotein; KW Reference proteome; Synapse. FT CHAIN 1..528 FT /note="Tyrosine 3-monooxygenase" FT /id="PRO_0000205561" FT REGION 33..65 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 361 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /evidence="ECO:0000250|UniProtKB:P04177" FT BINDING 366 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /evidence="ECO:0000250|UniProtKB:P04177" FT BINDING 406 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /evidence="ECO:0000250|UniProtKB:P04177" FT SITE 455 FT /note="Important for substrate specificity" FT /evidence="ECO:0000250|UniProtKB:P04177" FT MOD_RES 19 FT /note="Phosphoserine; by CaMK2" FT /evidence="ECO:0000269|PubMed:1680128, FT ECO:0000269|PubMed:24947669" FT MOD_RES 62 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:24947669, FT ECO:0000269|PubMed:28637871, ECO:0000269|PubMed:7901013" FT MOD_RES 71 FT /note="Phosphoserine; by CaMK2 and PKA" FT /evidence="ECO:0000269|PubMed:1680128, FT ECO:0000269|PubMed:7901013" FT MOD_RES 502 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P24529" FT VAR_SEQ 31..61 FT /note="Missing (in isoform 2 and isoform 6)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:17391063, ECO:0000303|PubMed:2882428" FT /id="VSP_000544" FT VAR_SEQ 31..34 FT /note="Missing (in isoform 1)" FT /evidence="ECO:0000303|PubMed:2888085" FT /id="VSP_000543" FT VAR_SEQ 35..61 FT /note="Missing (in isoform 4 and isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:17391063" FT /id="VSP_000541" FT VAR_SEQ 264..357 FT /note="Missing (in isoform 5 and isoform 6)" FT /evidence="ECO:0000303|PubMed:17391063" FT /id="VSP_054338" FT VARIANT 19 FT /note="S -> C (found in a patient with ARSEGS; uncertain FT significance; dbSNP:rs766704202)" FT /evidence="ECO:0000269|PubMed:23762320" FT /id="VAR_072862" FT VARIANT 112 FT /note="V -> M (in dbSNP:rs6356)" FT /evidence="ECO:0000269|PubMed:10391209, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:21940685, FT ECO:0000269|PubMed:7789962, ECO:0000269|PubMed:9613851" FT /id="VAR_014025" FT VARIANT 207 FT /note="C -> Y (in ARSEGS; loss of over 80% of tyrosine FT 3-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:20430833, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072863" FT VARIANT 227 FT /note="D -> G (in ARSEGS; complete loss of tyrosine FT 3-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:20430833, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072864" FT VARIANT 233 FT /note="R -> H (in ARSEGS; loss of over 80% of tyrosine FT 3-monooxygenase activity; shifted substrate specificity FT from tyrosine to phenylalanine and Dopa; dbSNP:rs80338892)" FT /evidence="ECO:0000269|PubMed:18554280, FT ECO:0000269|PubMed:22264700, ECO:0000269|PubMed:24753243, FT ECO:0000269|PubMed:9703425" FT /id="VAR_014026" FT VARIANT 236 FT /note="L -> P (in ARSEGS; severe parkinsonian symptoms in FT early infancy; strongly reduced stability and tyrosine FT 3-monooxygenase activity; rare mutation; FT dbSNP:rs121917763)" FT /evidence="ECO:0000269|PubMed:24753243, FT ECO:0000269|PubMed:8817341, ECO:0000269|PubMed:9613851" FT /id="VAR_014027" FT VARIANT 241 FT /note="A -> T (in ARSEGS; loss of over 80% of tyrosine FT 3-monooxygenase activity; dbSNP:rs1260455415)" FT /evidence="ECO:0000269|PubMed:20430833, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072865" FT VARIANT 246 FT /note="H -> Y (in ARSEGS; loss of about 40% of tyrosine FT 3-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:15747353, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072866" FT VARIANT 247 FT /note="G -> S (in ARSEGS; loss of about 50% of tyrosine FT 3-monooxygenase activity; shifted substrate specificity FT from tyrosine to phenylalanine and Dopa; FT dbSNP:rs762304556)" FT /evidence="ECO:0000269|PubMed:18554280, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072867" FT VARIANT 251 FT /note="P -> L (in ARSEGS)" FT /evidence="ECO:0000269|PubMed:21940685" FT /id="VAR_071715" FT VARIANT 259 FT /note="E -> G (in ARSEGS; complete loss of tyrosine FT 3-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:20430833, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072868" FT VARIANT 276 FT /note="T -> P (in ARSEGS; parkinsonian symptoms in infancy; FT no effect on tyrosine 3-monooxygenase activity; FT dbSNP:rs28934581)" FT /evidence="ECO:0000269|PubMed:11246459, FT ECO:0000269|PubMed:24753243" FT /id="VAR_014028" FT VARIANT 279 FT /note="C -> F (in ARSEGS; dbSNP:rs1273610334)" FT /evidence="ECO:0000269|PubMed:21940685" FT /id="VAR_071716" FT VARIANT 294 FT /note="G -> R (in ARSEGS; dbSNP:rs755536257)" FT /evidence="ECO:0000269|PubMed:20056467" FT /id="VAR_072869" FT VARIANT 296 FT /note="R -> Q (in ARSEGS; dbSNP:rs199961079)" FT /evidence="ECO:0000269|PubMed:21940685" FT /id="VAR_071717" FT VARIANT 301 FT /note="P -> A (in ARSEGS; loss of over 80% of tyrosine FT 3-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:19491146, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072870" FT VARIANT 309 FT /note="F -> S (in ARSEGS; complete loss of tyrosine FT 3-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:11196107, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072871" FT VARIANT 314 FT /note="T -> M (in ARSEGS; parkinsonian symptoms in infancy; FT loss of about 80% of tyrosine 3-monooxygenase activity; FT dbSNP:rs121917764)" FT /evidence="ECO:0000269|PubMed:11246459, FT ECO:0000269|PubMed:24753243" FT /id="VAR_014029" FT VARIANT 315 FT /note="G -> S (in ARSEGS; dbSNP:rs1288483479)" FT /evidence="ECO:0000269|PubMed:20056467, FT ECO:0000269|PubMed:22264700" FT /id="VAR_071718" FT VARIANT 319 FT /note="R -> P (in ARSEGS; complete loss of tyrosine FT 3-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:19491146, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072872" FT VARIANT 328 FT /note="R -> W (in ARSEGS; complete loss of tyrosine FT 3-monooxygenase activity; dbSNP:rs1428589694)" FT /evidence="ECO:0000269|PubMed:16049992, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072873" FT VARIANT 337 FT /note="R -> H (in ARSEGS; parkinsonian symptoms in infancy; FT no effect on tyrosine 3-monooxygenase activity; FT dbSNP:rs28934580)" FT /evidence="ECO:0000269|PubMed:11246459, FT ECO:0000269|PubMed:24753243" FT /id="VAR_014030" FT VARIANT 359 FT /note="C -> F (in ARSEGS; loss of over 80% of tyrosine FT 3-monooxygenase activity; dbSNP:rs121917765)" FT /evidence="ECO:0000269|PubMed:10585338, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072874" FT VARIANT 375 FT /note="F -> L (in ARSEGS; loss of over 80% of tyrosine FT 3-monooxygenase activity; shifted substrate specificity FT from tyrosine to phenylalanine and Dopa; FT dbSNP:rs763198914)" FT /evidence="ECO:0000269|PubMed:19491146, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072875" FT VARIANT 376 FT /note="A -> V (in ARSEGS; loss of over 80% of tyrosine FT 3-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:15505183, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072876" FT VARIANT 382 FT /note="I -> T (in ARSEGS; dbSNP:rs1554922725)" FT /evidence="ECO:0000269|PubMed:22264700" FT /id="VAR_071719" FT VARIANT 385 FT /note="A -> V (in ARSEGS; dbSNP:rs763039181)" FT /evidence="ECO:0000269|PubMed:20056467" FT /id="VAR_072877" FT VARIANT 387 FT /note="L -> M (in ARSEGS; no effect on tyrosine FT 3-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:17696123, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072878" FT VARIANT 394 FT /note="I -> T (in ARSEGS; complete loss of tyrosine FT 3-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:20056467, FT ECO:0000269|PubMed:20430833, ECO:0000269|PubMed:24753243" FT /id="VAR_072879" FT VARIANT 399 FT /note="T -> M (in ARSEGS; loss of over 80% of tyrosine FT 3-monooxygenase activity; dbSNP:rs1057520384)" FT /evidence="ECO:0000269|PubMed:16049992, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072880" FT VARIANT 408 FT /note="G -> R (in ARSEGS; dbSNP:rs745551241)" FT /evidence="ECO:0000269|PubMed:20056467" FT /id="VAR_072881" FT VARIANT 412 FT /note="Q -> K (in ARSEGS; loss of over 80% of tyrosine FT 3-monooxygenase activity; reduced affinity for L-tyrosine; FT dbSNP:rs121917762)" FT /evidence="ECO:0000269|PubMed:24753243, FT ECO:0000269|PubMed:7814018, ECO:0000269|PubMed:8528210" FT /id="VAR_014031" FT VARIANT 414 FT /note="G -> R (in ARSEGS; loss of over 80% of tyrosine FT 3-monooxygenase activity; dbSNP:rs370962049)" FT /evidence="ECO:0000269|PubMed:18058633, FT ECO:0000269|PubMed:19491146, ECO:0000269|PubMed:24753243" FT /id="VAR_072882" FT VARIANT 428 FT /note="G -> R (in ARSEGS; phenotype with prominent FT levodopa-responsive myoconus-dystonia (M-D); FT dbSNP:rs1264884607)" FT /evidence="ECO:0000269|PubMed:22815559, FT ECO:0000269|PubMed:23762320" FT /id="VAR_071720" FT VARIANT 441 FT /note="R -> P (in ARSEGS; complete loss of tyrosine FT 3-monooxygenase activity; dbSNP:rs367874223)" FT /evidence="ECO:0000269|PubMed:23939262, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072883" FT VARIANT 467 FT /note="S -> G (in ARSEGS; loss of over 80% of tyrosine FT 3-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:19491146, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072884" FT VARIANT 492 FT /note="P -> L (in ARSEGS; complete loss of tyrosine FT 3-monooxygenase activity; dbSNP:rs767635052)" FT /evidence="ECO:0000269|PubMed:17696123, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072885" FT VARIANT 494 FT /note="T -> M (in ARSEGS; parkinsonian symptoms in infancy; FT no effect on tyrosine 3-monooxygenase activity; FT dbSNP:rs45471299)" FT /evidence="ECO:0000269|PubMed:11246459, FT ECO:0000269|PubMed:24753243" FT /id="VAR_014032" FT VARIANT 498 FT /note="D -> G (in ARSEGS; loss of over 80% of tyrosine FT 3-monooxygenase activity; dbSNP:rs771351747)" FT /evidence="ECO:0000269|PubMed:15505183, FT ECO:0000269|PubMed:15747353, ECO:0000269|PubMed:23939262, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072886" FT VARIANT 499 FT /note="V -> M (in dbSNP:rs1800033)" FT /evidence="ECO:0000269|PubMed:9754624" FT /id="VAR_014033" FT VARIANT 510 FT /note="L -> Q (in ARSEGS; complete loss of tyrosine FT 3-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:18058633, FT ECO:0000269|PubMed:24753243" FT /id="VAR_072887" FT MUTAGEN 62 FT /note="S->A: Affects subcellular localization. Accumulates FT mainly in the soma of the neuroblastoma cells." FT /evidence="ECO:0000269|PubMed:28637871" FT MUTAGEN 62 FT /note="S->E: Does not affect subcellular localization. FT Distributed throughout the soma and neurites." FT /evidence="ECO:0000269|PubMed:28637871" FT MUTAGEN 71 FT /note="S->E: Suppresses feedback inhibition induced by FT dopamine. Suppresses feedback inhibition induced by FT dopamine; when associated with A-207." FT /evidence="ECO:0000269|PubMed:34922205" FT MUTAGEN 207 FT /note="C->A: Suppresses the decrease in tyrosine FT 3-monooxygenase activity induced by NEM modification. FT Suppresses feedback inhibition induced by dopamine; when FT associated with E-71." FT /evidence="ECO:0000269|PubMed:34922205" FT CONFLICT 373 FT /note="R -> H (in Ref. 8; AAI43615)" FT /evidence="ECO:0000305" FT CONFLICT 401 FT /note="Y -> S (in Ref. 1; AAA61179, 2; CAA28908 and 3; FT CAA68472)" FT /evidence="ECO:0000305" FT HELIX 201..206 FT /evidence="ECO:0007829|PDB:2XSN" FT TURN 216..218 FT /evidence="ECO:0007829|PDB:2XSN" FT TURN 223..226 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 228..243 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 257..277 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 280..292 FT /evidence="ECO:0007829|PDB:2XSN" FT STRAND 297..299 FT /evidence="ECO:0007829|PDB:6ZZU" FT HELIX 303..314 FT /evidence="ECO:0007829|PDB:2XSN" FT STRAND 317..320 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 327..334 FT /evidence="ECO:0007829|PDB:2XSN" FT TURN 335..337 FT /evidence="ECO:0007829|PDB:2XSN" FT STRAND 338..341 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 359..365 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 367..370 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 373..386 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 391..403 FT /evidence="ECO:0007829|PDB:2XSN" FT TURN 404..407 FT /evidence="ECO:0007829|PDB:2XSN" FT STRAND 409..412 FT /evidence="ECO:0007829|PDB:2XSN" FT STRAND 415..418 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 421..424 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 427..433 FT /evidence="ECO:0007829|PDB:2XSN" FT STRAND 435..442 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 445..449 FT /evidence="ECO:0007829|PDB:2XSN" FT STRAND 455..457 FT /evidence="ECO:0007829|PDB:2XSN" FT STRAND 460..466 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 468..480 FT /evidence="ECO:0007829|PDB:2XSN" FT STRAND 485..491 FT /evidence="ECO:0007829|PDB:2XSN" FT TURN 492..495 FT /evidence="ECO:0007829|PDB:2XSN" FT STRAND 496..500 FT /evidence="ECO:0007829|PDB:2XSN" FT HELIX 503..526 FT /evidence="ECO:0007829|PDB:2XSN" SQ SEQUENCE 528 AA; 58600 MW; 31D2D49955ACF070 CRC64; MPTPDATTPQ AKGFRRAVSE LDAKQAEAIM VRGQGAPGPS LTGSPWPGTA APAASYTPTP RSPRFIGRRQ SLIEDARKER EAAVAAAAAA VPSEPGDPLE AVAFEEKEGK AVLNLLFSPR ATKPSALSRA VKVFETFEAK IHHLETRPAQ RPRAGGPHLE YFVRLEVRRG DLAALLSGVR QVSEDVRSPA GPKVPWFPRK VSELDKCHHL VTKFDPDLDL DHPGFSDQVY RQRRKLIAEI AFQYRHGDPI PRVEYTAEEI ATWKEVYTTL KGLYATHACG EHLEAFALLE RFSGYREDNI PQLEDVSRFL KERTGFQLRP VAGLLSARDF LASLAFRVFQ CTQYIRHASS PMHSPEPDCC HELLGHVPML ADRTFAQFSQ DIGLASLGAS DEEIEKLSTL YWFTVEFGLC KQNGEVKAYG AGLLSSYGEL LHCLSEEPEI RAFDPEAAAV QPYQDQTYQS VYFVSESFSD AKDKLRSYAS RIQRPFSVKF DPYTLAIDVL DSPQAVRRSL EGVQDELDTL AHALSAIG //