ID GCH1_HUMAN Reviewed; 250 AA. AC P30793; Q6FHY7; Q9Y4I8; DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1993, sequence version 1. DT 27-MAR-2024, entry version 226. DE RecName: Full=GTP cyclohydrolase 1; DE EC=3.5.4.16 {ECO:0000269|PubMed:16778797, ECO:0000269|PubMed:2463916, ECO:0000269|PubMed:3753653}; DE AltName: Full=GTP cyclohydrolase I; DE Short=GTP-CH-I; GN Name=GCH1; Synonyms=DYT5, GCH; 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] (ISOFORMS GCH-1; GCH-2 AND GCH-3). RC TISSUE=Liver; RX PubMed=1520321; DOI=10.1016/s0006-291x(05)81501-3; RA Togari A., Ichinose H., Matsumoto S., Fujita K., Nagatsu T.; RT "Multiple mRNA forms of human GTP cyclohydrolase I."; RL Biochem. Biophys. Res. Commun. 187:359-365(1992). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS GCH-1 AND GCH-2), AND FUNCTION. RC TISSUE=Liver; RX PubMed=8068008; DOI=10.1042/bj3020215; RA Guetlich M., Jaeger E., Rucknaegel K.P., Werner T., Roedl W., Ziegler I., RA Bacher A.; RT "Human GTP cyclohydrolase I: only one out of three cDNA isoforms gives rise RT to the active enzyme."; RL Biochem. J. 302:215-221(1994). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Pheochromocytoma; RX PubMed=8695054; DOI=10.1007/bf01271561; RA Nomura T., Ohtsuki M., Matsui S., Sumi-Ichinose C., Nomura H., Hagino Y., RA Iwase K., Ichinose H., Fujita K., Nagatsu T.; RT "Isolation of a full-length cDNA clone for human GTP cyclohydrolase I type RT 1 from pheochromocytoma."; RL J. Neural Transm. 101:237-242(1995). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS GCH-1 AND GCH-4). RC TISSUE=Myelomonocyte; RX PubMed=11284739; DOI=10.1042/0264-6021:3550499; RA Golderer G., Werner E.R., Heufler C., Strohmaier W., Grobner P., RA Werner-Felmayer G.; RT "GTP cyclohydrolase I mRNA: novel splice variants in the slime mould RT Physarum polycephalum and in human monocytes (THP-1) indicate conservation RT of mRNA processing."; RL Biochem. J. 355:499-507(2001). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM GCH-1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [6] 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 [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM GCH-1). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-114. RC TISSUE=Granulocyte; RX PubMed=8666288; DOI=10.1016/0378-1119(95)00886-1; RA Witter K., Werner T., Blusch J.H., Schneider E.-M., Riess O., Ziegler I., RA Roedl W., Bacher A., Guetlich M.; RT "Cloning, sequencing and functional studies of the gene encoding human GTP RT cyclohydrolase I."; RL Gene 171:285-290(1996). RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 60-242. RX PubMed=1482676; DOI=10.1016/0167-4781(92)90112-d; RA Guetlich M., Schott K., Werner T., Bacher A., Ziegler I.; RT "Species and tissue specificity of mammalian GTP cyclohydrolase I messenger RT RNA."; RL Biochim. Biophys. Acta 1171:133-140(1992). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 116-209. RX PubMed=7730309; DOI=10.1074/jbc.270.17.10062; RA Ichinose H., Ohye T., Matsuda Y., Hori T.A., Blau N., Burlina A., Rouse B., RA Matalon R., Fujita K., Nagatsu T.; RT "Characterization of mouse and human GTP cyclohydrolase I genes. Mutations RT in patients with GTP cyclohydrolase I deficiency."; RL J. Biol. Chem. 270:10062-10071(1995). RN [11] RP ENZYME ACTIVITY, AND ACTIVITY REGULATION. RX PubMed=3753653; DOI=10.1016/0304-4165(86)90115-7; RA Blau N., Niederwieser A.; RT "The application of 8-aminoguanosine triphosphate, a new inhibitor of GTP RT cyclohydrolase I, to the purification of the enzyme from human liver."; RL Biochim. Biophys. Acta 880:26-31(1986). RN [12] RP BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=2500984; DOI=10.1016/0300-9084(89)90006-0; RA Shen R.-S., Alam A., Zhang Y.X.; RT "Human liver GTP cyclohydrolase I: purification and some properties."; RL Biochimie 71:343-349(1989). RN [13] RP ENZYME ACTIVITY, AND SUBCELLULAR LOCATION. RX PubMed=2463916; DOI=10.1111/j.1432-1033.1989.tb14491.x; RA Schoedon G., Redweik U., Curtius H.-C.; RT "Purification of GTP cyclohydrolase I from human liver and production of RT specific monoclonal antibodies."; RL Eur. J. Biochem. 178:627-634(1989). RN [14] RP INDUCTION. RX PubMed=7678411; DOI=10.1016/s0021-9258(18)53931-4; RA Werner-Felmayer G., Werner E.R., Fuchs D., Hausen A., Reibnegger G., RA Schmidt K., Weiss G., Wachter H.; RT "Pteridine biosynthesis in human endothelial cells. Impact on nitric oxide- RT mediated formation of cyclic GMP."; RL J. Biol. Chem. 268:1842-1846(1993). RN [15] RP REVIEW ON VARIANTS. RX PubMed=9222755; RX DOI=10.1002/(sici)1098-1004(1997)10:1<11::aid-humu2>3.0.co;2-p; RA Thoeny B., Blau N.; RT "Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin RT synthase genes."; RL Hum. Mutat. 10:11-20(1997). RN [16] RP FUNCTION, AND INDUCTION. RX PubMed=9445252; DOI=10.1161/01.atv.18.1.27; RA Katusic Z.S., Stelter A., Milstien S.; RT "Cytokines stimulate GTP cyclohydrolase I gene expression in cultured human RT umbilical vein endothelial cells."; RL Arterioscler. Thromb. Vasc. Biol. 18:27-32(1998). RN [17] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=12176133; DOI=10.1016/s0008-6363(02)00460-1; RA Cai S., Alp N.J., McDonald D., Smith I., Kay J., Canevari L., Heales S., RA Channon K.M.; RT "GTP cyclohydrolase I gene transfer augments intracellular RT tetrahydrobiopterin in human endothelial cells: effects on nitric oxide RT synthase activity, protein levels and dimerisation."; RL Cardiovasc. Res. 55:838-849(2002). RN [18] RP INDUCTION. RX PubMed=12002810; DOI=10.1016/s0024-3205(02)01503-5; RA Ohtsuki M., Shiraishi H., Kato T., Kuroda R., Tazawa M., Sumi-Ichinose C., RA Tada S., Udagawa Y., Itoh M., Hishida H., Ichinose H., Nagatsu T., RA Hagino Y., Nomura T.; RT "cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in RT human umbilical vein endothelial cells."; RL Life Sci. 70:2187-2198(2002). RN [19] RP INDUCTION. RX PubMed=12607127; DOI=10.1007/s00395-003-0394-y; RA Gesierich A., Niroomand F., Tiefenbacher C.P.; RT "Role of human GTP cyclohydrolase I and its regulatory protein in RT tetrahydrobiopterin metabolism."; RL Basic Res. Cardiol. 98:69-75(2003). RN [20] RP INDUCTION. RX PubMed=14646243; DOI=10.1254/jphs.93.265; RA Shiraishi H., Kato T., Atsuta K., Sumi-Ichinose C., Ohtsuki M., Itoh M., RA Hishida H., Tada S., Udagawa Y., Nagatsu T., Hagino Y., Ichinose H., RA Nomura T.; RT "cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of RT tetrahydrobiopterin in human umbilical vein endothelial cells."; RL J. Pharmacol. Sci. 93:265-271(2003). RN [21] RP ACTIVITY REGULATION. RX PubMed=14717702; DOI=10.1046/j.1432-1033.2003.03933.x; RA Suzuki T., Kurita H., Ichinose H.; RT "GTP cyclohydrolase I utilizes metal-free GTP as its substrate."; RL Eur. J. Biochem. 271:349-355(2004). RN [22] RP FUNCTION. RX PubMed=16338639; DOI=10.1016/j.brainresprot.2005.10.005; RA Duan C.-L., Su Y., Zhao C.-L., Lu L.-L., Xu Q.-Y., Yang H.; RT "The assays of activities and function of TH, AADC, and GCH1 and their RT potential use in ex vivo gene therapy of PD."; RL Brain Res. Brain Res. Protoc. 16:37-43(2005). RN [23] RP INDUCTION. RX PubMed=15604419; DOI=10.1161/01.res.0000153669.24827.df; RA Huang A., Zhang Y.-Y., Chen K., Hatakeyama K., Keaney J.F. Jr.; RT "Cytokine-stimulated GTP cyclohydrolase I expression in endothelial cells RT requires coordinated activation of nuclear factor-kappaB and Stat1/Stat3."; RL Circ. Res. 96:164-171(2005). RN [24] RP INDUCTION. RX PubMed=15649650; DOI=10.1016/j.freeradbiomed.2004.11.004; RA Kalivendi S., Hatakeyama K., Whitsett J., Konorev E., Kalyanaraman B., RA Vasquez-Vivar J.; RT "Changes in tetrahydrobiopterin levels in endothelial cells and adult RT cardiomyocytes induced by LPS and hydrogen peroxide -- a role for GFRP?"; RL Free Radic. Biol. Med. 38:481-491(2005). RN [25] RP SUBUNIT. RX PubMed=16848765; DOI=10.1042/bj20060765; RA Pandya M.J., Golderer G., Werner E.R., Werner-Felmayer G.; RT "Interaction of human GTP cyclohydrolase I with its splice variants."; RL Biochem. J. 400:75-80(2006). RN [26] RP ENZYME ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RX PubMed=16778797; DOI=10.1038/sj.jid.5700425; RA Chavan B., Gillbro J.M., Rokos H., Schallreuter K.U.; RT "GTP cyclohydrolase feedback regulatory protein controls cofactor 6- RT tetrahydrobiopterin synthesis in the cytosol and in the nucleus of RT epidermal keratinocytes and melanocytes."; RL J. Invest. Dermatol. 126:2481-2489(2006). RN [27] RP INTERACTION WITH AHSA1 AND GCHFR. RX PubMed=16696853; DOI=10.1111/j.1471-4159.2006.03836.x; RA Swick L., Kapatos G.; RT "A yeast 2-hybrid analysis of human GTP cyclohydrolase I protein RT interactions."; RL J. Neurochem. 97:1447-1455(2006). RN [28] RP FUNCTION. RX PubMed=17057711; DOI=10.1038/nm1490; RA Tegeder I., Costigan M., Griffin R.S., Abele A., Belfer I., Schmidt H., RA Ehnert C., Nejim J., Marian C., Scholz J., Wu T., Allchorne A., RA Diatchenko L., Binshtok A.M., Goldman D., Adolph J., Sama S., Atlas S.J., RA Carlezon W.A., Parsegian A., Loetsch J., Fillingim R.B., Maixner W., RA Geisslinger G., Max M.B., Woolf C.J.; RT "GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and RT persistence."; RL Nat. Med. 12:1269-1277(2006). RN [29] RP PHOSPHORYLATION AT SER-81. RX PubMed=17704208; DOI=10.1161/circresaha.107.153809; RA Widder J.D., Chen W., Li L., Dikalov S., Thony B., Hatakeyama K., RA Harrison D.G.; RT "Regulation of tetrahydrobiopterin biosynthesis by shear stress."; RL Circ. Res. 101:830-838(2007). RN [30] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-60, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [31] RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 55-250, SUBUNIT, AND ZINC-BINDING RP SITES. RX PubMed=11087827; DOI=10.1073/pnas.240463497; RA Auerbach G., Herrmann A., Bracher A., Bader G., Gutlich M., Fischer M., RA Neukamm M., Garrido-Franco M., Richardson J., Nar H., Huber R., Bacher A.; RT "Zinc plays a key role in human and bacterial GTP cyclohydrolase I."; RL Proc. Natl. Acad. Sci. U.S.A. 97:13567-13572(2000). RN [32] RP VARIANTS DRD TRP-88; VAL-134 AND GLU-201. RX PubMed=7874165; DOI=10.1038/ng1194-236; RA Ichinose H., Ohye T., Takahashi E., Seki N., Hori T., Segawa M., Nomura Y., RA Endo K., Tanaka H., Tsuji S., Fujita K., Nagatsu T.; RT "Hereditary progressive dystonia with marked diurnal fluctuation caused by RT mutations in the GTP cyclohydrolase I gene."; RL Nat. Genet. 8:236-242(1994). RN [33] RP VARIANT DRD PRO-79, AND VARIANTS HPABH4B HIS-184 AND ILE-211. RX PubMed=7501255; DOI=10.1016/0304-3940(95)11820-m; RA Ichinose H., Ohye T., Segawa M., Nomura Y., Endo K., Tanaka H., Tsuji S., RA Fujita K., Nagatsu T.; RT "GTP cyclohydrolase I gene in hereditary progressive dystonia with marked RT diurnal fluctuation."; RL Neurosci. Lett. 196:5-8(1995). RN [34] RP VARIANT DRD PRO-144. RX PubMed=8957022; DOI=10.1002/ana.410400517; RA Hirano M., Tamaru Y., Ito H., Matsumoto S., Imai T., Ueno S.; RT "Mutant GTP cyclohydrolase I mRNA levels contribute to dopa-responsive RT dystonia onset."; RL Ann. Neurol. 40:796-798(1996). RN [35] RP VARIANTS DRD PRO-88; PRO-153; ARG-203; ARG-224 AND SER-234. RX PubMed=8852666; DOI=10.1093/hmg/5.3.403; RA Bandmann O., Nygaard T.G., Surtess R., Mardsen C.D., Wood N.W., RA Harding A.E.; RT "Dopa-responsive dystonia in British patients: new mutations of the GTP- RT cyclohydrolase I gene and evidence for genetic heterogeneity."; RL Hum. Mol. Genet. 5:403-406(1996). RN [36] RP VARIANT DRD SER-178. RX PubMed=9120469; DOI=10.1136/jnnp.62.4.420; RA Beyer K., Lao-Villadoniga J.I., Vecino-Bilbao B., Cacabelos R., RA de la Fuent-Fernandez R.; RT "A novel point mutation in the GTP cyclohydrolase I gene in a Spanish RT family with hereditary progressive and dopa responsive dystonia."; RL J. Neurol. Neurosurg. Psych. 62:420-421(1997). RN [37] RP VARIANTS DRD LEU-23 AND ASN-115. RX PubMed=9328244; DOI=10.1136/jnnp.63.3.304; RA Jarman P.R., Bandmann O., Marsden C.D., Wood N.W.; RT "GTP cyclohydrolase I mutations in patients with dystonia responsive to RT anticholinergic drugs."; RL J. Neurol. Neurosurg. Psych. 63:304-308(1997). RN [38] RP VARIANTS HPABH4B ASP-108; THR-221 AND ARG-224. RX PubMed=9667588; DOI=10.1002/ana.410440107; RA Furukawa Y., Kish S.J., Bebin E.M., Jacobson R.D., Fryburg J.S., RA Wilson W.G., Shimadzu M., Hyland K., Trugman J.M.; RT "Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase RT I gene mutations."; RL Ann. Neurol. 44:10-16(1998). RN [39] RP VARIANTS DRD GLN-71; VAL-74; ALA-83; ILE-191; VAL-211 AND TRP-241. RX PubMed=9778264; DOI=10.1002/ana.410440411; RA Bandmann O., Valente E.M., Holmans P., Surtees R.A., Walters J.H., RA Wevers R.A., Marsden C.D., Wood N.W.; RT "Dopa-responsive dystonia: a clinical and molecular genetic study."; RL Ann. Neurol. 44:649-656(1998). RN [40] RP VARIANT DRD SER-249. RX PubMed=10987649; DOI=10.1007/s004390051093; RA Hwu W.-L., Wang P.-J., Hsiao K.-J., Wang T.-R., Chiou Y.-W., Lee Y.-M.; RT "Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I RT mutation."; RL Hum. Genet. 105:226-230(1999). RN [41] RP VARIANTS DRD ARG-102; LYS-102; ARG-141; TRP-141; THR-176; SER-178 AND RP LYS-186. RX PubMed=10582612; DOI=10.1046/j.1471-4159.1999.0732510.x; RA Suzuki T., Ohye T., Inagaki H., Nagatsu T., Ichinose H.; RT "Characterization of wild-type and mutants of recombinant human GTP RT cyclohydrolase I: relationship to etiology of dopa-responsive dystonia."; RL J. Neurochem. 73:2510-2516(1999). RN [42] RP VARIANT DRD LYS-135. RX PubMed=10208576; DOI=10.1097/00001756-199902250-00008; RA Brique S., Destee A., Lambert J.-C., Mouroux V., Delacourte A., Amouyel P., RA Chartier-Harlin M.-C.; RT "A new GTP-cyclohydrolase I mutation in an unusual dopa-responsive RT dystonia, familial form."; RL NeuroReport 10:487-491(1999). RN [43] RP VARIANT DRD VAL-90. RX PubMed=10076897; DOI=10.1016/s0304-3940(98)00984-7; RA Hirano M., Komure O., Ueno S.; RT "A novel missense mutant inactivates GTP cyclohydrolase I in dopa- RT responsive dystonia."; RL Neurosci. Lett. 260:181-184(1999). RN [44] RP VARIANTS DRD ALA-83; 88-ARG-GLN-89 DEL; SER-178; ARG-180; LEU-199 AND RP GLU-201. RX PubMed=10825351; DOI=10.1093/brain/123.6.1112; RA Tassin J., Duerr A., Bonnet A.-M., Gil R., Vidailhet M., Luecking C.B., RA Goas J.-Y., Durif F., Abada M., Echenne B., Motte J., Lagueny A., RA Lacomblez L., Jedynak P., Bartholome B., Agid Y., Brice A.; RT "Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations?"; RL Brain 123:1112-1121(2000). RN [45] RP VARIANTS DRD ARG-163 AND VAL-213. RX PubMed=11113234; DOI=10.1212/wnl.55.11.1735; RA Steinberger D., Korinthenberg R., Topka H., Berghaeuser M., Wedde R., RA Mueller U.; RT "Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of RT therapeutic doses of L-dopa. German Dystonia Study Group."; RL Neurology 55:1735-1737(2000). RN [46] RP VARIANT DRD ARG-224. RX PubMed=12391354; DOI=10.1212/wnl.59.8.1241; RA Leuzzi V., Carducci C., Carducci C., Cardona F., Artiola C., Antonozzi I.; RT "Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive RT myoclonus-dystonia syndrome."; RL Neurology 59:1241-1243(2002). RN [47] RP VARIANT DRD ILE-106. RX PubMed=17101830; DOI=10.1001/archneur.63.11.1605; RA Ohta E., Funayama M., Ichinose H., Toyoshima I., Urano F., Matsuo M., RA Tomoko N., Yukihiko K., Yoshino S., Yokoyama H., Shimazu H., Maeda K., RA Hasegawa K., Obata F.; RT "Novel mutations in the guanosine triphosphate cyclohydrolase 1 gene RT associated with DYT5 dystonia."; RL Arch. Neurol. 63:1605-1610(2006). RN [48] RP VARIANTS CYS-75; VAL-98 AND THR-135. 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). CC -!- FUNCTION: Positively regulates nitric oxide synthesis in umbilical vein CC endothelial cells (HUVECs). May be involved in dopamine synthesis. May CC modify pain sensitivity and persistence. Isoform GCH-1 is the CC functional enzyme, the potential function of the enzymatically inactive CC isoforms remains unknown. {ECO:0000269|PubMed:12176133, CC ECO:0000269|PubMed:16338639, ECO:0000269|PubMed:17057711, CC ECO:0000269|PubMed:8068008, ECO:0000269|PubMed:9445252}. CC -!- CATALYTIC ACTIVITY: CC Reaction=GTP + H2O = 7,8-dihydroneopterin 3'-triphosphate + formate + CC H(+); Xref=Rhea:RHEA:17473, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:15740, ChEBI:CHEBI:37565, ChEBI:CHEBI:58462; EC=3.5.4.16; CC Evidence={ECO:0000269|PubMed:16778797, ECO:0000269|PubMed:2463916, CC ECO:0000269|PubMed:3753653}; CC -!- ACTIVITY REGULATION: GTP shows a positive allosteric effect, and CC tetrahydrobiopterin inhibits the enzyme activity. Zinc is required for CC catalytic activity. Inhibited by Mg(2+). {ECO:0000269|PubMed:14717702, CC ECO:0000269|PubMed:16778797, ECO:0000269|PubMed:3753653}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=116 uM for GTP {ECO:0000269|PubMed:2500984}; CC pH dependence: CC Optimum pH is 7.7 in phosphate buffer. {ECO:0000269|PubMed:2500984}; CC Temperature dependence: CC Relatively stable at high temperatures. Retains 50% of its activity CC after incubation at 70 degrees Celsius for 15 minutes. CC {ECO:0000269|PubMed:2500984}; CC -!- PATHWAY: Cofactor biosynthesis; 7,8-dihydroneopterin triphosphate CC biosynthesis; 7,8-dihydroneopterin triphosphate from GTP: step 1/1. CC {ECO:0000305|PubMed:16778797, ECO:0000305|PubMed:2463916, CC ECO:0000305|PubMed:3753653}. CC -!- SUBUNIT: Toroid-shaped homodecamer, composed of a dimer of pentamers. CC The inactive isoforms also form decamers and may possibly be CC incorporated into GCH1 heterodecamers, decreasing enzyme stability and CC activity. Interacts with AHSA1 and GCHFR/GFRP. CC {ECO:0000269|PubMed:11087827, ECO:0000269|PubMed:16696853, CC ECO:0000269|PubMed:16848765}. CC -!- INTERACTION: CC P30793; O95433: AHSA1; NbExp=3; IntAct=EBI-958183, EBI-448610; CC P30793; O14787-2: TNPO2; NbExp=3; IntAct=EBI-958183, EBI-12076664; CC P30793; Q9Y5L0: TNPO3; NbExp=3; IntAct=EBI-958183, EBI-1042571; CC P30793; P63104: YWHAZ; NbExp=4; IntAct=EBI-958183, EBI-347088; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12176133, CC ECO:0000269|PubMed:16778797, ECO:0000269|PubMed:2463916}. Nucleus CC {ECO:0000269|PubMed:16778797}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=GCH-1; CC IsoId=P30793-1; Sequence=Displayed; CC Name=GCH-2; CC IsoId=P30793-2; Sequence=VSP_001612, VSP_001613; CC Name=GCH-3; CC IsoId=P30793-3; Sequence=VSP_001610; CC Name=GCH-4; CC IsoId=P30793-4; Sequence=VSP_001611, VSP_001614; CC -!- TISSUE SPECIFICITY: In epidermis, expressed predominantly in basal CC undifferentiated keratinocytes and in some but not all melanocytes (at CC protein level). {ECO:0000269|PubMed:16778797}. CC -!- INDUCTION: Up-regulated by IFNG/IFN-gamma, TNF, IL1B/interleukin-1 CC beta, bacterial lipopolysaccharides (LPS) and phenylalanine, and down- CC regulated by dibutyryl-cAMP, iloprost and 8-bromo-cGMP in HUVEC cells. CC Up-regulation of GCH1 expression, in turn, stimulates production of CC tetrahydrobiopterin, with subsequent elevation of endothelial nitric CC oxide synthase activity. Cytokine-induced GCH1 up-regulation in HUVECs CC in response to TNF and IFNG/IFN-gamma involves cooperative activation CC of both the NF-kappa-B and JAK2/STAT pathways. Also up-regulated by CC hydrogen peroxide in human aorta endothelial cells (HAECs). CC {ECO:0000269|PubMed:12002810, ECO:0000269|PubMed:12607127, CC ECO:0000269|PubMed:14646243, ECO:0000269|PubMed:15604419, CC ECO:0000269|PubMed:15649650, ECO:0000269|PubMed:7678411, CC ECO:0000269|PubMed:9445252}. CC -!- PTM: Phosphorylated by casein kinase II at Ser-81 in HAECs during CC oscillatory shear stress; phosphorylation at Ser-81 results in CC increased enzyme activity. {ECO:0000269|PubMed:17704208}. CC -!- DISEASE: Hyperphenylalaninemia, BH4-deficient, B (HPABH4B) CC [MIM:233910]: A disease characterized by malignant CC hyperphenylalaninemia due to tetrahydrobiopterin deficiency, and CC defective neurotransmission due to depletion of the neurotransmitters CC dopamine and serotonin. The principal symptoms include: psychomotor CC retardation, tonicity disorders, convulsions, drowsiness, irritability, CC abnormal movements, hyperthermia, hypersalivation, and difficulty CC swallowing. Some patients may present a phenotype of intermediate CC severity between severe hyperphenylalaninemia and mild dystonia. In CC this intermediate phenotype, there is marked motor delay, but no CC intellectual disability and only minimal, if any, CC hyperphenylalaninemia. {ECO:0000269|PubMed:7501255, CC ECO:0000269|PubMed:9667588}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Dystonia, dopa-responsive (DRD) [MIM:128230]: A form of CC dystonia that responds to L-DOPA treatment without side effects. CC Dystonia is defined by the presence of sustained involuntary muscle CC contractions, often leading to abnormal postures. DRD typically CC presents in childhood with walking problems due to dystonia of the CC lower limbs and worsening of the dystonia towards the evening. It is CC characterized by postural and motor disturbances showing marked diurnal CC fluctuation. Torsion of the trunk is unusual. Symptoms are alleviated CC after sleep and aggravated by fatigue and exercise. CC {ECO:0000269|PubMed:10076897, ECO:0000269|PubMed:10208576, CC ECO:0000269|PubMed:10582612, ECO:0000269|PubMed:10825351, CC ECO:0000269|PubMed:10987649, ECO:0000269|PubMed:11113234, CC ECO:0000269|PubMed:12391354, ECO:0000269|PubMed:17101830, CC ECO:0000269|PubMed:7501255, ECO:0000269|PubMed:7874165, CC ECO:0000269|PubMed:8852666, ECO:0000269|PubMed:8957022, CC ECO:0000269|PubMed:9120469, ECO:0000269|PubMed:9328244, CC ECO:0000269|PubMed:9778264}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the GTP cyclohydrolase I family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; S44049; AAB23164.1; -; mRNA. DR EMBL; S44053; AAB23165.1; -; mRNA. DR EMBL; S43856; AAB23166.1; -; mRNA. DR EMBL; Z29433; CAB77391.1; -; mRNA. DR EMBL; Z29434; CAB77392.1; -; mRNA. DR EMBL; U19523; AAB16861.1; -; mRNA. DR EMBL; U66095; AAD38866.1; -; mRNA. DR EMBL; U66097; AAD38868.1; -; mRNA. DR EMBL; CR536551; CAG38788.1; -; mRNA. DR EMBL; CH471061; EAW80647.1; -; Genomic_DNA. DR EMBL; BC025415; AAH25415.1; -; mRNA. DR EMBL; L29478; AAB42186.1; -; Genomic_DNA. DR EMBL; Z30952; CAA83213.1; -; Genomic_DNA. DR EMBL; Z16418; CAA78908.1; -; mRNA. DR EMBL; U19259; AAB60633.1; -; Genomic_DNA. DR EMBL; U19256; AAB60633.1; JOINED; Genomic_DNA. DR EMBL; U19257; AAB60633.1; JOINED; Genomic_DNA. DR EMBL; U19258; AAB60633.1; JOINED; Genomic_DNA. DR CCDS; CCDS41954.1; -. [P30793-4] DR CCDS; CCDS45110.1; -. [P30793-2] DR CCDS; CCDS9720.1; -. [P30793-1] DR PIR; G01630; PC1117. DR PIR; JC1225; JC1225. DR RefSeq; NP_000152.1; NM_000161.2. [P30793-1] DR RefSeq; NP_001019195.1; NM_001024024.1. [P30793-1] DR RefSeq; NP_001019241.1; NM_001024070.1. [P30793-4] DR RefSeq; NP_001019242.1; NM_001024071.1. [P30793-2] DR PDB; 1FB1; X-ray; 3.10 A; A/B/C/D/E=55-250. DR PDB; 6Z80; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=41-250. DR PDB; 6Z85; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=41-250. DR PDB; 6Z86; X-ray; 2.21 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T=41-250. DR PDB; 6Z87; X-ray; 2.56 A; A/B/C/D/E=41-250. DR PDB; 6Z88; X-ray; 2.69 A; A/B/C/D/E/F/G/H/I/J=41-250. DR PDB; 6Z89; X-ray; 2.37 A; A/B/C/D/E=41-250. DR PDB; 7ALA; X-ray; 1.85 A; A/B/C/D/E=42-250. DR PDB; 7ALB; X-ray; 1.98 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T=42-250. DR PDB; 7ALC; X-ray; 1.73 A; A/B/C/D/E=42-250. DR PDB; 7ALQ; X-ray; 2.21 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T=42-250. DR PDBsum; 1FB1; -. DR PDBsum; 6Z80; -. DR PDBsum; 6Z85; -. DR PDBsum; 6Z86; -. DR PDBsum; 6Z87; -. DR PDBsum; 6Z88; -. DR PDBsum; 6Z89; -. DR PDBsum; 7ALA; -. DR PDBsum; 7ALB; -. DR PDBsum; 7ALC; -. DR PDBsum; 7ALQ; -. DR AlphaFoldDB; P30793; -. DR SMR; P30793; -. DR BioGRID; 108913; 68. DR IntAct; P30793; 33. DR MINT; P30793; -. DR STRING; 9606.ENSP00000477796; -. DR DrugBank; DB02377; Guanine. DR iPTMnet; P30793; -. DR PhosphoSitePlus; P30793; -. DR BioMuta; GCH1; -. DR DMDM; 399536; -. DR EPD; P30793; -. DR MassIVE; P30793; -. DR MaxQB; P30793; -. DR PaxDb; 9606-ENSP00000419045; -. DR PeptideAtlas; P30793; -. DR ProteomicsDB; 54735; -. [P30793-1] DR ProteomicsDB; 54736; -. [P30793-2] DR ProteomicsDB; 54737; -. [P30793-3] DR ProteomicsDB; 54738; -. [P30793-4] DR Pumba; P30793; -. DR Antibodypedia; 23963; 407 antibodies from 35 providers. DR DNASU; 2643; -. DR Ensembl; ENST00000395514.5; ENSP00000378890.1; ENSG00000131979.20. [P30793-1] DR Ensembl; ENST00000491895.7; ENSP00000419045.2; ENSG00000131979.20. [P30793-1] DR Ensembl; ENST00000536224.2; ENSP00000445246.2; ENSG00000131979.20. [P30793-2] DR Ensembl; ENST00000543643.6; ENSP00000444011.2; ENSG00000131979.20. [P30793-4] DR GeneID; 2643; -. DR KEGG; hsa:2643; -. DR MANE-Select; ENST00000491895.7; ENSP00000419045.2; NM_000161.3; NP_000152.1. DR UCSC; uc001xbh.2; human. [P30793-1] DR AGR; HGNC:4193; -. DR CTD; 2643; -. DR DisGeNET; 2643; -. DR GeneCards; GCH1; -. DR GeneReviews; GCH1; -. DR HGNC; HGNC:4193; GCH1. DR HPA; ENSG00000131979; Tissue enhanced (bone marrow, liver). DR MalaCards; GCH1; -. DR MIM; 128230; phenotype. DR MIM; 233910; phenotype. DR MIM; 600225; gene. DR neXtProt; NX_P30793; -. DR OpenTargets; ENSG00000131979; -. DR Orphanet; 98808; Autosomal dominant dopa-responsive dystonia. DR Orphanet; 2102; GTP cyclohydrolase I deficiency. DR PharmGKB; PA28608; -. DR VEuPathDB; HostDB:ENSG00000131979; -. DR eggNOG; KOG2698; Eukaryota. DR GeneTree; ENSGT00390000013481; -. DR HOGENOM; CLU_049768_1_3_1; -. DR InParanoid; P30793; -. DR OMA; CEHMCMS; -. DR OrthoDB; 1009at2759; -. DR PhylomeDB; P30793; -. DR TreeFam; TF105616; -. DR BioCyc; MetaCyc:HS05586-MONOMER; -. DR BRENDA; 3.5.4.16; 2681. DR PathwayCommons; P30793; -. DR Reactome; R-HSA-1474151; Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation. DR SABIO-RK; P30793; -. DR SignaLink; P30793; -. DR SIGNOR; P30793; -. DR UniPathway; UPA00848; UER00151. DR BioGRID-ORCS; 2643; 15 hits in 1174 CRISPR screens. DR ChiTaRS; GCH1; human. DR EvolutionaryTrace; P30793; -. DR GeneWiki; GTP_cyclohydrolase_I; -. DR GenomeRNAi; 2643; -. DR Pharos; P30793; Tbio. DR PRO; PR:P30793; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; P30793; Protein. DR Bgee; ENSG00000131979; Expressed in secondary oocyte and 184 other cell types or tissues. DR ExpressionAtlas; P30793; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl. DR GO; GO:0044306; C:neuron projection terminus; TAS:ParkinsonsUK-UCL. DR GO; GO:0031965; C:nuclear membrane; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0005509; F:calcium ion binding; IEA:Ensembl. DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB. DR GO; GO:0003934; F:GTP cyclohydrolase I activity; IDA:UniProtKB. DR GO; GO:0030742; F:GTP-dependent protein binding; IEA:Ensembl. DR GO; GO:0003924; F:GTPase activity; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB. DR GO; GO:0051019; F:mitogen-activated protein kinase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:0035998; P:7,8-dihydroneopterin 3'-triphosphate biosynthetic process; IEA:UniProtKB-UniPathway. DR GO; GO:0042416; P:dopamine biosynthetic process; IDA:UniProtKB. DR GO; GO:0045776; P:negative regulation of blood pressure; IEA:Ensembl. DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IEA:Ensembl. DR GO; GO:2000773; P:negative regulation of cellular senescence; IEA:Ensembl. DR GO; GO:0050884; P:neuromuscular process controlling posture; IMP:MGI. DR GO; GO:0006809; P:nitric oxide biosynthetic process; NAS:UniProtKB. DR GO; GO:0010460; P:positive regulation of heart rate; IEA:Ensembl. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0051000; P:positive regulation of nitric-oxide synthase activity; IDA:UniProtKB. DR GO; GO:0032212; P:positive regulation of telomere maintenance via telomerase; IEA:Ensembl. DR GO; GO:0065003; P:protein-containing complex assembly; IEA:Ensembl. DR GO; GO:0042559; P:pteridine-containing compound biosynthetic process; IDA:UniProtKB. DR GO; GO:0008217; P:regulation of blood pressure; IMP:UniProtKB. DR GO; GO:0014916; P:regulation of lung blood pressure; IEA:Ensembl. DR GO; GO:2000121; P:regulation of removal of superoxide radicals; IMP:BHF-UCL. DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:UniProtKB. DR GO; GO:0048265; P:response to pain; ISS:UniProtKB. DR GO; GO:0034612; P:response to tumor necrosis factor; IDA:UniProtKB. DR GO; GO:0034341; P:response to type II interferon; IDA:UniProtKB. DR GO; GO:0006729; P:tetrahydrobiopterin biosynthetic process; IDA:UniProtKB. DR GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IEA:InterPro. DR GO; GO:0042311; P:vasodilation; IEA:Ensembl. DR CDD; cd00642; GTP_cyclohydro1; 1. DR Gene3D; 1.10.286.10; -; 1. DR Gene3D; 3.30.1130.10; -; 1. DR HAMAP; MF_00223; FolE; 1. DR InterPro; IPR043133; GTP-CH-I_C/QueF. DR InterPro; IPR043134; GTP-CH-I_N. DR InterPro; IPR001474; GTP_CycHdrlase_I. DR InterPro; IPR018234; GTP_CycHdrlase_I_CS. DR InterPro; IPR020602; GTP_CycHdrlase_I_dom. DR NCBIfam; TIGR00063; folE; 1. DR PANTHER; PTHR11109:SF11; GTP CYCLOHYDROLASE 1; 1. DR PANTHER; PTHR11109; GTP CYCLOHYDROLASE I; 1. DR Pfam; PF01227; GTP_cyclohydroI; 1. DR SUPFAM; SSF55620; Tetrahydrobiopterin biosynthesis enzymes-like; 1. DR PROSITE; PS00859; GTP_CYCLOHYDROL_1_1; 1. DR PROSITE; PS00860; GTP_CYCLOHYDROL_1_2; 1. DR Genevisible; P30793; HS. PE 1: Evidence at protein level; KW 3D-structure; Allosteric enzyme; Alternative splicing; Cytoplasm; KW Disease variant; Dystonia; GTP-binding; Hydrolase; Metal-binding; KW Nucleotide-binding; Nucleus; Parkinsonism; Phenylketonuria; Phosphoprotein; KW Reference proteome; Tetrahydrobiopterin biosynthesis; Zinc. FT CHAIN 1..250 FT /note="GTP cyclohydrolase 1" FT /id="PRO_0000119478" FT REGION 1..64 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 50..64 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 141 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:11087827" FT BINDING 144 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:11087827" FT BINDING 212 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:11087827" FT MOD_RES 60 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 81 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:17704208" FT VAR_SEQ 210..250 FT /note="Missing (in isoform GCH-3)" FT /evidence="ECO:0000303|PubMed:1520321" FT /id="VSP_001610" FT VAR_SEQ 210..233 FT /note="HMCMVMRGVQKMNSKTVTSTMLGV -> KSNKYNKGLSPLLSSCHLFVAILK FT (in isoform GCH-4)" FT /evidence="ECO:0000303|PubMed:11284739" FT /id="VSP_001611" FT VAR_SEQ 210..213 FT /note="HMCM -> SAEP (in isoform GCH-2)" FT /evidence="ECO:0000303|PubMed:1520321, FT ECO:0000303|PubMed:8068008" FT /id="VSP_001612" FT VAR_SEQ 214..250 FT /note="Missing (in isoform GCH-2)" FT /evidence="ECO:0000303|PubMed:1520321, FT ECO:0000303|PubMed:8068008" FT /id="VSP_001613" FT VAR_SEQ 234..250 FT /note="Missing (in isoform GCH-4)" FT /evidence="ECO:0000303|PubMed:11284739" FT /id="VSP_001614" FT VARIANT 15 FT /note="G -> D (in HGCH-3)" FT /id="VAR_002632" FT VARIANT 23 FT /note="P -> L (in DRD; dbSNP:rs41298432)" FT /evidence="ECO:0000269|PubMed:9328244" FT /id="VAR_002633" FT VARIANT 71 FT /note="L -> Q (in DRD)" FT /evidence="ECO:0000269|PubMed:9778264" FT /id="VAR_016888" FT VARIANT 74 FT /note="A -> V (in DRD)" FT /evidence="ECO:0000269|PubMed:9778264" FT /id="VAR_016889" FT VARIANT 75 FT /note="Y -> C (found in patients with DRD; uncertain FT significance)" FT /id="VAR_072733" FT VARIANT 79 FT /note="L -> P (in DRD)" FT /evidence="ECO:0000269|PubMed:7501255" FT /id="VAR_002634" FT VARIANT 83 FT /note="G -> A (in DRD)" FT /evidence="ECO:0000269|PubMed:10825351, FT ECO:0000269|PubMed:9778264" FT /id="VAR_016890" FT VARIANT 88..89 FT /note="Missing (in DRD)" FT /evidence="ECO:0000269|PubMed:10825351" FT /id="VAR_016891" FT VARIANT 88 FT /note="R -> P (in DRD)" FT /evidence="ECO:0000269|PubMed:8852666" FT /id="VAR_002635" FT VARIANT 88 FT /note="R -> W (in DRD; dbSNP:rs104894433)" FT /evidence="ECO:0000269|PubMed:7874165" FT /id="VAR_002636" FT VARIANT 90 FT /note="G -> V (in DRD)" FT /evidence="ECO:0000269|PubMed:10076897" FT /id="VAR_016892" FT VARIANT 98 FT /note="A -> V" FT /id="VAR_072734" FT VARIANT 102 FT /note="M -> K (in DRD)" FT /evidence="ECO:0000269|PubMed:10582612" FT /id="VAR_002637" FT VARIANT 102 FT /note="M -> R (in DRD)" FT /evidence="ECO:0000269|PubMed:10582612" FT /id="VAR_016893" FT VARIANT 106 FT /note="T -> I (in DRD)" FT /evidence="ECO:0000269|PubMed:17101830" FT /id="VAR_054112" FT VARIANT 108 FT /note="G -> D (in HPABH4B; intermediate phenotype FT presenting with dystonia and motor delay; FT dbSNP:rs104894435)" FT /evidence="ECO:0000269|PubMed:9667588" FT /id="VAR_016894" FT VARIANT 115 FT /note="D -> N (in DRD; dbSNP:rs1393095176)" FT /evidence="ECO:0000269|PubMed:9328244" FT /id="VAR_016895" FT VARIANT 134 FT /note="D -> V (in DRD; dbSNP:rs104894437)" FT /evidence="ECO:0000269|PubMed:7874165" FT /id="VAR_002638" FT VARIANT 135 FT /note="I -> K (in DRD; dbSNP:rs104894441)" FT /evidence="ECO:0000269|PubMed:10208576" FT /id="VAR_016896" FT VARIANT 135 FT /note="I -> T" FT /id="VAR_072735" FT VARIANT 141 FT /note="C -> R (in DRD)" FT /evidence="ECO:0000269|PubMed:10582612" FT /id="VAR_016897" FT VARIANT 141 FT /note="C -> W (in DRD)" FT /evidence="ECO:0000269|PubMed:10582612" FT /id="VAR_002639" FT VARIANT 144 FT /note="H -> P (in DRD; dbSNP:rs104894440)" FT /evidence="ECO:0000269|PubMed:8957022" FT /id="VAR_002640" FT VARIANT 153 FT /note="H -> P (in DRD)" FT /evidence="ECO:0000269|PubMed:8852666" FT /id="VAR_002641" FT VARIANT 163 FT /note="L -> R (in DRD)" FT /evidence="ECO:0000269|PubMed:11113234" FT /id="VAR_016898" FT VARIANT 176 FT /note="S -> T (in DRD)" FT /evidence="ECO:0000269|PubMed:10582612" FT /id="VAR_016899" FT VARIANT 178 FT /note="R -> S (in DRD)" FT /evidence="ECO:0000269|PubMed:10582612, FT ECO:0000269|PubMed:10825351, ECO:0000269|PubMed:9120469" FT /id="VAR_002642" FT VARIANT 180 FT /note="Q -> R (in DRD)" FT /evidence="ECO:0000269|PubMed:10825351" FT /id="VAR_016900" FT VARIANT 184 FT /note="R -> H (in HPABH4B; severe hyperphenylalaninemia; FT dbSNP:rs104894445)" FT /evidence="ECO:0000269|PubMed:7501255" FT /id="VAR_002643" FT VARIANT 186 FT /note="T -> K (in DRD)" FT /evidence="ECO:0000269|PubMed:10582612" FT /id="VAR_002644" FT VARIANT 191 FT /note="V -> I (in DRD; dbSNP:rs762208304)" FT /evidence="ECO:0000269|PubMed:9778264" FT /id="VAR_016901" FT VARIANT 199 FT /note="P -> L (in DRD)" FT /evidence="ECO:0000269|PubMed:10825351" FT /id="VAR_016902" FT VARIANT 201 FT /note="G -> E (in DRD; dbSNP:rs104894438)" FT /evidence="ECO:0000269|PubMed:10825351, FT ECO:0000269|PubMed:7874165" FT /id="VAR_002645" FT VARIANT 203 FT /note="G -> R (in DRD; dbSNP:rs988395114)" FT /evidence="ECO:0000269|PubMed:8852666" FT /id="VAR_002646" FT VARIANT 211 FT /note="M -> I (in HPABH4B; severe hyperphenylalaninemia; FT dbSNP:rs104894443)" FT /evidence="ECO:0000269|PubMed:7501255" FT /id="VAR_002647" FT VARIANT 211 FT /note="M -> V (in DRD)" FT /evidence="ECO:0000269|PubMed:9778264" FT /id="VAR_016903" FT VARIANT 213 FT /note="M -> V (in DRD; dbSNP:rs1348562494)" FT /evidence="ECO:0000269|PubMed:11113234" FT /id="VAR_016904" FT VARIANT 221 FT /note="M -> T (in HPABH4B; intermediate phenotype FT presenting with dystonia and motor delay; FT dbSNP:rs104894434)" FT /evidence="ECO:0000269|PubMed:9667588" FT /id="VAR_016905" FT VARIANT 224 FT /note="K -> R (in HPABH4B and DRD; phenotype presenting FT with dystonia and myoclonus; dbSNP:rs41298442)" FT /evidence="ECO:0000269|PubMed:12391354, FT ECO:0000269|PubMed:8852666, ECO:0000269|PubMed:9667588" FT /id="VAR_002648" FT VARIANT 234 FT /note="F -> S (in DRD)" FT /evidence="ECO:0000269|PubMed:8852666" FT /id="VAR_002649" FT VARIANT 241 FT /note="R -> W (in DRD; dbSNP:rs1375209791)" FT /evidence="ECO:0000269|PubMed:9778264" FT /id="VAR_016906" FT VARIANT 249 FT /note="R -> S (in DRD; dbSNP:rs104894442)" FT /evidence="ECO:0000269|PubMed:10987649" FT /id="VAR_016907" FT CONFLICT 11 FT /note="E -> G (in Ref. 4; AAD38866)" FT /evidence="ECO:0000305" FT CONFLICT 206 FT /note="V -> I (in Ref. 9; CAA78908)" FT /evidence="ECO:0000305" FT HELIX 61..81 FT /evidence="ECO:0007829|PDB:7ALC" FT STRAND 86..88 FT /evidence="ECO:0007829|PDB:6Z85" FT HELIX 89..91 FT /evidence="ECO:0007829|PDB:7ALC" FT HELIX 94..105 FT /evidence="ECO:0007829|PDB:7ALC" FT HELIX 107..110 FT /evidence="ECO:0007829|PDB:7ALC" FT HELIX 113..116 FT /evidence="ECO:0007829|PDB:7ALC" FT TURN 117..119 FT /evidence="ECO:0007829|PDB:7ALC" FT STRAND 121..123 FT /evidence="ECO:0007829|PDB:7ALC" FT STRAND 129..141 FT /evidence="ECO:0007829|PDB:7ALC" FT TURN 142..144 FT /evidence="ECO:0007829|PDB:7ALC" FT STRAND 147..157 FT /evidence="ECO:0007829|PDB:7ALC" FT STRAND 159..163 FT /evidence="ECO:0007829|PDB:7ALC" FT HELIX 165..176 FT /evidence="ECO:0007829|PDB:7ALC" FT STRAND 177..180 FT /evidence="ECO:0007829|PDB:7ALC" FT HELIX 182..197 FT /evidence="ECO:0007829|PDB:7ALC" FT STRAND 200..210 FT /evidence="ECO:0007829|PDB:7ALC" FT HELIX 211..213 FT /evidence="ECO:0007829|PDB:7ALB" FT TURN 215..217 FT /evidence="ECO:0007829|PDB:1FB1" FT STRAND 224..232 FT /evidence="ECO:0007829|PDB:7ALC" FT HELIX 233..236 FT /evidence="ECO:0007829|PDB:7ALC" FT HELIX 238..247 FT /evidence="ECO:0007829|PDB:7ALC" SQ SEQUENCE 250 AA; 27903 MW; B8A0CB344C598B9A CRC64; MEKGPVRAPA EKPRGARCSN GFPERDPPRP GPSRPAEKPP RPEAKSAQPA DGWKGERPRS EEDNELNLPN LAAAYSSILS SLGENPQRQG LLKTPWRAAS AMQFFTKGYQ ETISDVLNDA IFDEDHDEMV IVKDIDMFSM CEHHLVPFVG KVHIGYLPNK QVLGLSKLAR IVEIYSRRLQ VQERLTKQIA VAITEALRPA GVGVVVEATH MCMVMRGVQK MNSKTVTSTM LGVFREDPKT REEFLTLIRS //