GCH1_HUMAN
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 03-AUG-2022, entry version 218.
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 ---------------------------------------------------------------------------
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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.ENSP00000419045; -.
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; P30793; -.
DR PeptideAtlas; P30793; -.
DR PRIDE; P30793; -.
DR ProteomicsDB; 54735; -. [P30793-1]
DR ProteomicsDB; 54736; -. [P30793-2]
DR ProteomicsDB; 54737; -. [P30793-3]
DR ProteomicsDB; 54738; -. [P30793-4]
DR Antibodypedia; 23963; 359 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 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 PhylomeDB; P30793; -.
DR TreeFam; TF105616; -.
DR BioCyc; MetaCyc:HS05586-MON; -.
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; 14 hits in 1092 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 182 other tissues.
DR ExpressionAtlas; P30793; baseline and differential.
DR Genevisible; P30793; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
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:0031369; F:translation initiation factor 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: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:0051000; P:positive regulation of nitric-oxide synthase activity; IDA:UniProtKB.
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: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:Ensembl.
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 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; 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; unknown
FT pathological 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
