TY3H_HUMAN
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 03-AUG-2022, entry version 231.
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>3.0.co;2-z;
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>3.0.co;2-p;
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 ---------------------------------------------------------------------------
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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 SASBDB; P07101; -.
DR SMR; P07101; -.
DR BioGRID; 112912; 38.
DR ELM; P07101; -.
DR IntAct; P07101; 22.
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; P07101; -.
DR PeptideAtlas; P07101; -.
DR PRIDE; 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; 1700 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 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; PELDMNH; -.
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; 8 hits in 1075 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 104 other tissues.
DR ExpressionAtlas; P07101; baseline and differential.
DR Genevisible; P07101; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
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:0010259; P:multicellular organism aging; IEA:Ensembl.
DR GO; GO:0042136; P:neurotransmitter biosynthetic process; IEA:UniProtKB-KW.
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:0009414; P:response to water deprivation; IEA:Ensembl.
DR GO; GO:0010043; P:response to zinc ion; IEA:Ensembl.
DR GO; GO:0007605; P:sensory perception of sound; 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; cd03345; eu_TyrOH; 1.
DR Gene3D; 1.10.800.10; -; 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; IPR005962; Tyr_3_mOase.
DR InterPro; IPR019773; Tyrosine_3-monooxygenase-like.
DR InterPro; IPR021164; Tyrosine_hydroxylase_CS.
DR PANTHER; PTHR11473; PTHR11473; 1.
DR Pfam; PF00351; Biopterin_H; 1.
DR Pfam; PF12549; TOH_N; 3.
DR PIRSF; PIRSF000336; TH; 1.
DR PRINTS; PR00372; FYWHYDRXLASE.
DR SUPFAM; SSF55021; SSF55021; 1.
DR SUPFAM; SSF56534; SSF56534; 1.
DR TIGRFAMs; TIGR01269; Tyr_3_monoox; 1.
DR PROSITE; PS00367; BH4_AAA_HYDROXYL_1; 1.
DR PROSITE; PS51410; BH4_AAA_HYDROXYL_2; 1.
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; unknown
FT pathological 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 3-
FT 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 3-
FT 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 3-
FT monooxygenase activity; shifted substrate specificity from
FT 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 3-
FT monooxygenase activity; rare mutation; 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 3-
FT 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 3-
FT 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 3-
FT monooxygenase activity; shifted substrate specificity from
FT tyrosine to phenylalanine and Dopa; 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT monooxygenase activity; shifted substrate specificity from
FT tyrosine to phenylalanine and Dopa; 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT 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 3-
FT 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
