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 28-NOV-2012, entry version 142. DE RecName: Full=GTP cyclohydrolase 1; DE EC=3.5.4.16; 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS GCH-1; GCH-2 AND GCH-3). RC TISSUE=Liver; RX MEDLINE=92392350; 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 MEDLINE=94347104; PubMed=8068008; RA Guetlich M., Jaeger E., Rucknaegel K.P., Werner T., Roedl W., RA Ziegler I., Bacher A.; RT "Human GTP cyclohydrolase I: only one out of three cDNA isoforms gives RT rise to the active enzyme."; RL Biochem. J. 302:215-221(1994). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Pheochromocytoma; RX MEDLINE=96274939; PubMed=8695054; DOI=10.1007/BF01271561; RA Nomura T., Ohtsuki M., Matsui S., Sumi-Ichinose C., Nomura H., RA Hagino Y., Iwase K., Ichinose H., Fujita K., Nagatsu T.; RT "Isolation of a full-length cDNA clone for human GTP cyclohydrolase I RT type 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 RT conservation 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., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA 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 RT project: 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 MEDLINE=96257235; PubMed=8666288; DOI=10.1016/0378-1119(95)00886-1; RA Witter K., Werner T., Blusch J.H., Schneider E.-M., Riess O., RA Ziegler I., Roedl W., Bacher A., Guetlich M.; RT "Cloning, sequencing and functional studies of the gene encoding human RT GTP cyclohydrolase I."; RL Gene 171:285-290(1996). RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 60-242. RX MEDLINE=93129611; PubMed=1482676; RA Guetlich M., Schott K., Werner T., Bacher A., Ziegler I.; RT "Species and tissue specificity of mammalian GTP cyclohydrolase I RT messenger RNA."; RL Biochim. Biophys. Acta 1171:133-140(1992). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 116-209. RX MEDLINE=95247712; PubMed=7730309; DOI=10.1074/jbc.270.17.10062; RA Ichinose H., Ohye T., Matsuda Y., Hori T.A., Blau N., Burlina A., RA Rouse B., Matalon R., Fujita K., Nagatsu T.; RT "Characterization of mouse and human GTP cyclohydrolase I genes. RT Mutations in patients with GTP cyclohydrolase I deficiency."; RL J. Biol. Chem. 270:10062-10071(1995). RN [11] RP ENZYME ACTIVITY, AND ENZYME 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 RT GTP cyclohydrolase I, to the purification of the enzyme from human RT 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 RT of specific monoclonal antibodies."; RL Eur. J. Biochem. 178:627-634(1989). RN [14] RP INDUCTION. RX PubMed=7678411; 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 RT oxide-mediated formation of cyclic GMP."; RL J. Biol. Chem. 268:1842-1846(1993). RN [15] RP REVIEW ON VARIANTS. RX MEDLINE=97365928; PubMed=9222755; RX DOI=10.1002/(SICI)1098-1004(1997)10:1<11::AID-HUMU2>3.3.CO;2-C; 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; RA Katusic Z.S., Stelter A., Milstien S.; RT "Cytokines stimulate GTP cyclohydrolase I gene expression in cultured RT human 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., RA Heales S., Channon K.M.; RT "GTP cyclohydrolase I gene transfer augments intracellular RT tetrahydrobiopterin in human endothelial cells: effects on nitric RT oxide 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., RA Sumi-Ichinose C., Tada S., Udagawa Y., Itoh M., Hishida H., RA Ichinose H., Nagatsu T., 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., RA Itoh M., Hishida H., Tada S., Udagawa Y., Nagatsu T., Hagino Y., RA Ichinose H., 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 ENZYME 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 RT cells requires coordinated activation of nuclear factor-kappaB and RT 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 RT 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, ENZYME 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., RA Schmidt H., Ehnert C., Nejim J., Marian C., Scholz J., Wu T., RA Allchorne A., Diatchenko L., Binshtok A.M., Goldman D., Adolph J., RA Sama S., Atlas S.J., Carlezon W.A., Parsegian A., Loetsch J., RA Fillingim R.B., Maixner W., Geisslinger G., Max M.B., Woolf C.J.; RT "GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity RT and 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 MASS RP SPECTROMETRY. 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 RP ZINC-BINDING SITES. RX PubMed=11087827; DOI=10.1073/pnas.240463497; RA Auerbach G., Herrmann A., Bracher A., Bader G., Gutlich M., RA Fischer M., Neukamm M., Garrido-Franco M., Richardson J., Nar H., RA 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 DYT5 TRP-88; VAL-134 AND GLU-201. RX MEDLINE=95179168; PubMed=7874165; DOI=10.1038/ng1194-236; RA Ichinose H., Ohye T., Takahashi E., Seki N., Hori T., Segawa M., RA Nomura Y., Endo K., Tanaka H., Tsuji S., Fujita K., Nagatsu T.; RT "Hereditary progressive dystonia with marked diurnal fluctuation RT caused by mutations in the GTP cyclohydrolase I gene."; RL Nat. Genet. 8:236-242(1994). RN [33] RP VARIANT DYT5 PRO-79, AND VARIANTS GCH1D HIS-184 AND ILE-211. RX MEDLINE=96053062; PubMed=7501255; DOI=10.1016/0304-3940(95)11820-M; RA Ichinose H., Ohye T., Segawa M., Nomura Y., Endo K., Tanaka H., RA Tsuji S., Fujita K., Nagatsu T.; RT "GTP cyclohydrolase I gene in hereditary progressive dystonia with RT marked diurnal fluctuation."; RL Neurosci. Lett. 196:5-8(1995). RN [34] RP VARIANT DYT5 PRO-144. RX MEDLINE=97115903; 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 DYT5 PRO-88; PRO-153; ARG-203; ARG-224 AND SER-234. RX MEDLINE=97005367; 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 RT GTP-cyclohydrolase I gene and evidence for genetic heterogeneity."; RL Hum. Mol. Genet. 5:403-406(1996). RN [36] RP VARIANT DYT5 SER-178. RX MEDLINE=97252592; PubMed=9120469; 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 DYT5 LEU-23 AND ASN-115. RX MEDLINE=97466904; PubMed=9328244; RA Jarman P.R., Bandmann O., Marsden C.D., Wood N.W.; RT "GTP cyclohydrolase I mutations in patients with dystonia responsive RT to anticholinergic drugs."; RL J. Neurol. Neurosurg. Psych. 63:304-308(1997). RN [38] RP VARIANTS GCH1D ASP-108; THR-221 AND ARG-224. RX MEDLINE=98330162; 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- RT cyclohydrolase I gene mutations."; RL Ann. Neurol. 44:10-16(1998). RN [39] RP VARIANTS DYT5 GLN-71; VAL-74; ALA-83; ILE-191; VAL-211 AND TRP-241. RX MEDLINE=98449713; 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 DYT5 SER-249. RX MEDLINE=20441956; PubMed=10987649; DOI=10.1007/s004390051093; RA Hwu W.-L., Wang P.-J., Hsiao K.-J., Wang T.-R., Chiou Y.-W., RA 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 DYT5 ARG-102; LYS-102; ARG-141; TRP-141; THR-176; SER-178 AND RP LYS-186. RX MEDLINE=20047437; PubMed=10582612; RX 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 RT dystonia."; RL J. Neurochem. 73:2510-2516(1999). RN [42] RP VARIANT DYT5 LYS-135. RX MEDLINE=99223275; PubMed=10208576; RA Brique S., Destee A., Lambert J.-C., Mouroux V., Delacourte A., RA Amouyel P., 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 DYT5 VAL-90. RX MEDLINE=99174515; 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 DYT5 ALA-83; 88-ARG-GLN-89 DEL; SER-178; ARG-180; LEU-199 AND RP GLU-201. RX MEDLINE=20340247; PubMed=10825351; DOI=10.1093/brain/123.6.1112; RA Tassin J., Duerr A., Bonnet A.-M., Gil R., Vidailhet M., RA Luecking C.B., Goas J.-Y., Durif F., Abada M., Echenne B., Motte J., RA Lagueny A., Lacomblez L., Jedynak P., Bartholome B., Agid Y., RA Brice A.; RT "Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin RT mutations?"; RL Brain 123:1112-1121(2000). RN [45] RP VARIANTS DYT5 ARG-163 AND VAL-213. RX MEDLINE=20565823; PubMed=11113234; 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 DYT5 ARG-224. RX MEDLINE=22278969; PubMed=12391354; RA Leuzzi V., Carducci C., Carducci C., Cardona F., Artiola C., RA 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 DYT5 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). CC -!- FUNCTION: Positively regulates nitric oxide synthesis in umbilical CC vein endothelial cells (HUVECs). May be involved in dopamine CC synthesis. May modify pain sensitivity and persistence. Isoform CC GCH-1 is the functional enzyme, the potential function of the CC enzymatically inactive isoforms remains unknown. CC -!- CATALYTIC ACTIVITY: GTP + H(2)O = formate + 2-amino-4-hydroxy-6- CC (erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate. CC -!- ENZYME REGULATION: GTP shows a positive allosteric effect, and CC tetrahydrobiopterin inhibits the enzyme activity. Zinc is required CC for catalytic activity. Inhibited by Mg(2+). CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=116 uM for GTP; CC pH dependence: CC Optimum pH is 7.7 in phosphate buffer; CC Temperature dependence: CC Relatively stable at high temperatures. Retains 50% of its CC activity after incubation at 70 degrees Celsius for 15 minutes; CC -!- PATHWAY: Cofactor biosynthesis; 7,8-dihydroneopterin triphosphate CC biosynthesis; 7,8-dihydroneopterin triphosphate from GTP: step CC 1/1. CC -!- SUBUNIT: Toroid-shaped homodecamer, composed of a dimer of CC pentamers. The inactive isoforms also form decamers and may CC possibly be incorporated into GCH1 heterodecamers, decreasing CC enzyme stability and activity. Interacts with AHSA1 and CC GCHFR/GFRP. CC -!- INTERACTION: CC O95433:AHSA1; NbExp=3; IntAct=EBI-958183, EBI-448610; CC P63104:YWHAZ; NbExp=4; IntAct=EBI-958183, EBI-347088; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. 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 CC (at protein level). CC -!- INDUCTION: Up-regulated by IFNG/IFN-gamma, TNF, IL1B/interleukin-1 CC beta, bacterial lipopolysaccharides (LPS) and phenylalanine, and CC down-regulated by dibutyryl-cAMP, iloprost and 8-bromo-cGMP in CC HUVEC cells. Up-regulation of GCH1 expression, in turn, stimulates CC production of tetrahydrobiopterin, with subsequent elevation of CC endothelial nitric oxide synthase activity. Cytokine-induced GCH1 CC up-regulation in HUVECs in response to TNF and IFNG/IFN-gamma CC involves cooperative activation of both the NF-kappa-B and CC JAK2/STAT pathways. Also up-regulated by hydrogen peroxide in CC human aorta endothelial cells (HAECs). 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. CC -!- DISEASE: Defects in GCH1 are the cause of GTP cyclohydrolase 1 CC deficiency (GCH1D) [MIM:233910]; also known as atypical severe CC phenylketonuria due to GTP cyclohydrolase I deficiency;. GCH1D is CC one of the causes of malignant hyperphenylalaninemia due to CC tetrahydrobiopterin deficiency. It is also responsible for CC defective neurotransmission due to depletion of the CC neurotransmitters dopamine and serotonin. The principal symptoms CC include: psychomotor retardation, tonicity disorders, convulsions, CC drowsiness, irritability, abnormal movements, hyperthermia, CC hypersalivation, and difficulty swallowing. Some patients may CC present a phenotype of intermediate severity between severe CC hyperphenylalaninemia and mild dystonia type 5 (dystonia- CC parkinsonism with diurnal fluctuation). In this intermediate CC phenotype, there is marked motor delay, but no mental retardation CC and only minimal, if any, hyperphenylalaninemia. CC -!- DISEASE: Defects in GCH1 are the cause of dystonia type 5 (DYT5) CC [MIM:128230]; also known as progressive dystonia with diurnal CC fluctuation, autosomal dominant Segawa syndrome or dystonia- CC parkinsonism with diurnal fluctuation. DYT5 is a DOPA-responsive CC dystonia. Dystonia is defined by the presence of sustained CC involuntary muscle contractions, often leading to abnormal CC postures. DYT5 typically presents in childhood with walking CC problems due to dystonia of the lower limbs and worsening of the CC dystonia towards the evening. It is characterized by postural and CC motor disturbances showing marked diurnal fluctuation. Torsion of CC the trunk is unusual. Symptoms are alleviated after sleep and CC aggravated by fatigue and excercise. There is a favorable response CC to L-DOPA without side effects. CC -!- SIMILARITY: Belongs to the GTP cyclohydrolase I family. CC -!- WEB RESOURCE: Name=BIOMDB; Note=Db of mutations causing CC tetrahydrobiopterin deficiencies; CC URL="http://www.bh4.org/biodef1.html"; CC -!- WEB RESOURCE: Name=GeneReviews; CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GCH1"; 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 IPI; IPI00027492; -. DR IPI; IPI00220702; -. DR IPI; IPI00220703; -. DR IPI; IPI00335632; -. DR PIR; G01630; PC1117. DR PIR; JC1225; JC1225. DR RefSeq; NP_000152.1; NM_000161.2. DR RefSeq; NP_001019195.1; NM_001024024.1. DR RefSeq; NP_001019241.1; NM_001024070.1. DR RefSeq; NP_001019242.1; NM_001024071.1. DR UniGene; Hs.86724; -. DR PDB; 1FB1; X-ray; 3.10 A; A/B/C/D/E=55-250. DR PDBsum; 1FB1; -. DR ProteinModelPortal; P30793; -. DR SMR; P30793; 55-250. DR IntAct; P30793; 10. DR STRING; P30793; -. DR PhosphoSite; P30793; -. DR DMDM; 399536; -. DR PRIDE; P30793; -. DR DNASU; 2643; -. DR Ensembl; ENST00000395514; ENSP00000378890; ENSG00000131979. DR Ensembl; ENST00000491895; ENSP00000419045; ENSG00000131979. DR Ensembl; ENST00000536224; ENSP00000445246; ENSG00000131979. DR Ensembl; ENST00000543643; ENSP00000444011; ENSG00000131979. DR GeneID; 2643; -. DR KEGG; hsa:2643; -. DR UCSC; uc001xbh.1; human. DR UCSC; uc001xbj.1; human. DR UCSC; uc001xbk.1; human. DR CTD; 2643; -. DR GeneCards; GC14M055308; -. DR HGNC; HGNC:4193; GCH1. DR HPA; HPA028612; -. DR MIM; 128230; phenotype. DR MIM; 233910; phenotype. DR MIM; 600225; gene. DR neXtProt; NX_P30793; -. DR Orphanet; 98808; Autosomal dominant dopa-responsive dystonia. DR Orphanet; 2102; GTP cyclohydrolase I deficiency. DR PharmGKB; PA28608; -. DR eggNOG; COG0302; -. DR HOGENOM; HOG000221222; -. DR HOVERGEN; HBG003136; -. DR InParanoid; P30793; -. DR KO; K01495; -. DR OMA; KQIATAM; -. DR OrthoDB; EOG4FR0SK; -. DR PhylomeDB; P30793; -. DR BioCyc; MetaCyc:HS05586-MONOMER; -. DR Reactome; REACT_111217; Metabolism. DR UniPathway; UPA00848; UER00151. DR EvolutionaryTrace; P30793; -. DR GenomeRNAi; 2643; -. DR NextBio; 10420; -. DR ArrayExpress; P30793; -. DR Bgee; P30793; -. DR CleanEx; HS_GCH1; -. DR Genevestigator; P30793; -. DR GermOnline; ENSG00000131979; Homo sapiens. DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0031965; C:nuclear membrane; IDA:HPA. DR GO; GO:0043234; C:protein complex; IDA:UniProtKB. DR GO; GO:0005509; F:calcium ion binding; IEA:Compara. DR GO; GO:0050662; F:coenzyme binding; IEA:Compara. DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB. DR GO; GO:0003934; F:GTP cyclohydrolase I activity; IDA:UniProtKB. 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:0051066; P:dihydrobiopterin metabolic process; IEA:Compara. DR GO; GO:0042416; P:dopamine biosynthetic process; IDA:UniProtKB. DR GO; GO:0006184; P:GTP catabolic process; IDA:UniProtKB. DR GO; GO:0006917; P:induction of apoptosis; IEA:Compara. DR GO; GO:0045776; P:negative regulation of blood pressure; IEA:Compara. 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:0051000; P:positive regulation of nitric-oxide synthase activity; IDA:UniProtKB. DR GO; GO:0051291; P:protein heterooligomerization; IEA:Compara. DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB. DR GO; GO:0008217; P:regulation of blood pressure; IMP:UniProtKB. DR GO; GO:0014916; P:regulation of lung blood pressure; IEA:Compara. DR GO; GO:0034341; P:response to interferon-gamma; IDA:UniProtKB. 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:0006729; P:tetrahydrobiopterin biosynthetic process; IDA:UniProtKB. DR GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IEA:InterPro. DR GO; GO:0042311; P:vasodilation; IEA:Compara. DR InterPro; IPR001474; GTP_CycHdrlase_I. DR InterPro; IPR020602; GTP_CycHdrlase_I/CN_OxRdtase. DR InterPro; IPR018234; GTP_CycHdrlase_I_CS. DR PANTHER; PTHR11109; PTHR11109; 1. DR Pfam; PF01227; GTP_cyclohydroI; 1. DR TIGRFAMs; TIGR00063; folE; 1. DR PROSITE; PS00859; GTP_CYCLOHYDROL_1_1; 1. DR PROSITE; PS00860; GTP_CYCLOHYDROL_1_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Allosteric enzyme; Alternative splicing; KW Complete proteome; Cytoplasm; Disease mutation; Dystonia; GTP-binding; KW Hydrolase; Metal-binding; Nucleotide-binding; Nucleus; Parkinsonism; KW Phenylketonuria; Phosphoprotein; Polymorphism; Reference proteome; KW Tetrahydrobiopterin biosynthesis; Zinc. FT CHAIN 1 250 GTP cyclohydrolase 1. FT /FTId=PRO_0000119478. FT METAL 141 141 Zinc. FT METAL 144 144 Zinc. FT METAL 212 212 Zinc. FT MOD_RES 60 60 Phosphoserine. FT MOD_RES 81 81 Phosphoserine. FT VAR_SEQ 210 250 Missing (in isoform GCH-3). FT /FTId=VSP_001610. FT VAR_SEQ 210 233 HMCMVMRGVQKMNSKTVTSTMLGV -> KSNKYNKGLSPLL FT SSCHLFVAILK (in isoform GCH-4). FT /FTId=VSP_001611. FT VAR_SEQ 210 213 HMCM -> SAEP (in isoform GCH-2). FT /FTId=VSP_001612. FT VAR_SEQ 214 250 Missing (in isoform GCH-2). FT /FTId=VSP_001613. FT VAR_SEQ 234 250 Missing (in isoform GCH-4). FT /FTId=VSP_001614. FT VARIANT 15 15 G -> D (in HGCH-3). FT /FTId=VAR_002632. FT VARIANT 23 23 P -> L (in DYT5; dbSNP:rs41298432). FT /FTId=VAR_002633. FT VARIANT 71 71 L -> Q (in DYT5). FT /FTId=VAR_016888. FT VARIANT 74 74 A -> V (in DYT5). FT /FTId=VAR_016889. FT VARIANT 79 79 L -> P (in DYT5). FT /FTId=VAR_002634. FT VARIANT 83 83 G -> A (in DYT5). FT /FTId=VAR_016890. FT VARIANT 88 89 Missing (in DYT5). FT /FTId=VAR_016891. FT VARIANT 88 88 R -> P (in DYT5). FT /FTId=VAR_002635. FT VARIANT 88 88 R -> W (in DYT5). FT /FTId=VAR_002636. FT VARIANT 90 90 G -> V (in DYT5). FT /FTId=VAR_016892. FT VARIANT 102 102 M -> K (in DYT5). FT /FTId=VAR_002637. FT VARIANT 102 102 M -> R (in DYT5). FT /FTId=VAR_016893. FT VARIANT 106 106 T -> I (in DYT5). FT /FTId=VAR_054112. FT VARIANT 108 108 G -> D (in GCH1D; phenotype presenting FT with dystonia and motor delay). FT /FTId=VAR_016894. FT VARIANT 115 115 D -> N (in DYT5). FT /FTId=VAR_016895. FT VARIANT 134 134 D -> V (in DYT5). FT /FTId=VAR_002638. FT VARIANT 135 135 I -> K (in DYT5). FT /FTId=VAR_016896. FT VARIANT 141 141 C -> R (in DYT5). FT /FTId=VAR_016897. FT VARIANT 141 141 C -> W (in DYT5). FT /FTId=VAR_002639. FT VARIANT 144 144 H -> P (in DYT5). FT /FTId=VAR_002640. FT VARIANT 153 153 H -> P (in DYT5). FT /FTId=VAR_002641. FT VARIANT 163 163 L -> R (in DYT5). FT /FTId=VAR_016898. FT VARIANT 176 176 S -> T (in DYT5). FT /FTId=VAR_016899. FT VARIANT 178 178 R -> S (in DYT5). FT /FTId=VAR_002642. FT VARIANT 180 180 Q -> R (in DYT5). FT /FTId=VAR_016900. FT VARIANT 184 184 R -> H (in GCH1D; severe FT hyperphenylalaninemia). FT /FTId=VAR_002643. FT VARIANT 186 186 T -> K (in DYT5). FT /FTId=VAR_002644. FT VARIANT 191 191 V -> I (in DYT5). FT /FTId=VAR_016901. FT VARIANT 199 199 P -> L (in DYT5). FT /FTId=VAR_016902. FT VARIANT 201 201 G -> E (in DYT5). FT /FTId=VAR_002645. FT VARIANT 203 203 G -> R (in DYT5). FT /FTId=VAR_002646. FT VARIANT 211 211 M -> I (in GCH1D; severe FT hyperphenylalaninemia). FT /FTId=VAR_002647. FT VARIANT 211 211 M -> V (in DYT5). FT /FTId=VAR_016903. FT VARIANT 213 213 M -> V (in DYT5). FT /FTId=VAR_016904. FT VARIANT 221 221 M -> T (in GCH1D; a patient presenting FT with dystonia and motor delay; compound FT heterozygote for an additional deletion). FT /FTId=VAR_016905. FT VARIANT 224 224 K -> R (in GCH1D and DYT5; phenotype FT presenting with dystonia and myoclonus; FT dbSNP:rs41298442). FT /FTId=VAR_002648. FT VARIANT 234 234 F -> S (in DYT5). FT /FTId=VAR_002649. FT VARIANT 241 241 R -> W (in DYT5). FT /FTId=VAR_016906. FT VARIANT 249 249 R -> S (in DYT5). FT /FTId=VAR_016907. FT CONFLICT 11 11 E -> G (in Ref. 4; AAD38866). FT CONFLICT 206 206 V -> I (in Ref. 9; CAA78908). FT HELIX 61 81 FT HELIX 91 93 FT HELIX 94 102 FT TURN 103 106 FT HELIX 108 110 FT TURN 113 115 FT STRAND 130 141 FT TURN 142 144 FT STRAND 147 156 FT HELIX 165 176 FT STRAND 177 180 FT HELIX 182 197 FT STRAND 202 210 FT HELIX 211 214 FT TURN 215 217 FT STRAND 224 230 FT HELIX 233 236 FT HELIX 238 248 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 //