GTP cyclohydrolase 1

NameGTP cyclohydrolase 1
Synonyms
  • 3.5.4.16
  • DYT5
  • GCH
  • GTP cyclohydrolase I
  • GTP-CH-I
Gene NameGCH1
OrganismHuman
Amino acid sequence
>lcl|BSEQ0002101|GTP cyclohydrolase 1
MEKGPVRAPAEKPRGARCSNGFPERDPPRPGPSRPAEKPPRPEAKSAQPADGWKGERPRS
EEDNELNLPNLAAAYSSILSSLGENPQRQGLLKTPWRAASAMQFFTKGYQETISDVLNDA
IFDEDHDEMVIVKDIDMFSMCEHHLVPFVGKVHIGYLPNKQVLGLSKLARIVEIYSRRLQ
VQERLTKQIAVAITEALRPAGVGVVVEATHMCMVMRGVQKMNSKTVTSTMLGVFREDPKT
REEFLTLIRS
Number of residues250
Molecular Weight27902.855
Theoretical pI8.82
GO Classification
Functions
  • GTP binding
  • calcium ion binding
  • GTP cyclohydrolase I activity
  • protein homodimerization activity
  • coenzyme binding
  • zinc ion binding
Processes
  • regulation of blood pressure
  • response to tumor necrosis factor
  • protein homooligomerization
  • response to pain
  • tetrahydrofolate biosynthetic process
  • neuromuscular process controlling posture
  • nitric oxide biosynthetic process
  • nitric oxide metabolic process
  • regulation of nitric-oxide synthase activity
  • small molecule metabolic process
  • response to interferon-gamma
  • tetrahydrobiopterin biosynthetic process
  • dopamine biosynthetic process
  • vasodilation
  • response to lipopolysaccharide
  • 7,8-dihydroneopterin 3'-triphosphate biosynthetic process
  • negative regulation of blood pressure
  • pteridine-containing compound biosynthetic process
  • positive regulation of nitric-oxide synthase activity
  • regulation of lung blood pressure
  • protein heterooligomerization
  • regulation of removal of superoxide radicals
Components
  • cytoplasm
  • protein complex
  • nucleus
  • cytoplasmic vesicle
  • cytosol
  • nuclear membrane
  • nucleoplasm
General FunctionZinc ion binding
Specific FunctionPositively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein ID7242659
UniProtKB IDP30793
UniProtKB Entry NameGCH1_HUMAN
Cellular LocationCytoplasm
Gene sequence
>lcl|BSEQ0010741|GTP cyclohydrolase 1 (GCH1)
ATGGAGAAGGGCCCTGTGCGGGCACCGGCGGAGAAGCCGCGGGGCGCCAGGTGCAGCAAT
GGGTTCCCCGAGCGGGATCCGCCGCGGCCCGGGCCCAGCAGGCCGGCGGAGAAGCCCCCG
CGGCCCGAGGCCAAGAGCGCGCAGCCCGCGGACGGCTGGAAGGGCGAGCGGCCCCGCAGC
GAGGAGGATAACGAGCTGAACCTCCCTAACCTGGCAGCCGCCTACTCGTCCATCCTGAGC
TCGCTGGGCGAGAACCCCCAGCGGCAAGGGCTGCTCAAGACGCCCTGGAGGGCGGCCTCG
GCCATGCAGTTCTTCACCAAGGGCTACCAGGAGACCATCTCAGATGTCCTAAACGATGCT
ATATTTGATGAAGATCATGATGAGATGGTGATTGTGAAGGACATAGACATGTTTTCCATG
TGTGAGCATCACTTGGTTCCATTTGTTGGAAAGGTCCATATTGGTTATCTTCCTAACAAG
CAAGTCCTTGGCCTCAGCAAACTTGCGAGGATTGTAGAAATCTATAGTAGAAGACTACAA
GTTCAGGAGCGCCTTACAAAACAAATTGCTGTAGCAATCACGGAAGCCTTGCGGCCTGCT
GGAGTCGGGGTAGTGGTTGAAGCAACACACATGTGTATGGTAATGCGAGGTGTACAGAAA
ATGAACAGCAAAACTGTGACCAGCACAATGTTGGGTGTGTTCCGGGAGGATCCAAAGACT
CGGGAAGAGTTCCTGACTCTCATTAGGAGCTGA
GenBank Gene IDZ29434
GeneCard IDNot Available
GenAtlas IDGCH1
HGNC IDHGNC:4193
Chromosome Location14
Locus14q22.1-q22.2
References
  1. Togari A, Ichinose H, Matsumoto S, Fujita K, Nagatsu T: Multiple mRNA forms of human GTP cyclohydrolase I. Biochem Biophys Res Commun. 1992 Aug 31;187(1):359-65. 1520321
  2. Gutlich M, Jaeger E, Rucknagel KP, Werner T, Rodl W, Ziegler I, Bacher A: Human GTP cyclohydrolase I: only one out of three cDNA isoforms gives rise to the active enzyme. Biochem J. 1994 Aug 15;302 ( Pt 1):215-21. 8068008
  3. Nomura T, Ohtsuki M, Matsui S, Sumi-Ichinose C, Nomura H, Hagino Y, Iwase K, Ichinose H, Fujita K, Nagatsu T: Isolation of a full-length cDNA clone for human GTP cyclohydrolase I type 1 from pheochromocytoma. J Neural Transm Gen Sect. 1995;101(1-3):237-42. 8695054
  4. Golderer G, Werner ER, Heufler C, Strohmaier W, Grobner P, Werner-Felmayer G: GTP cyclohydrolase I mRNA: novel splice variants in the slime mould Physarum polycephalum and in human monocytes (THP-1) indicate conservation of mRNA processing. Biochem J. 2001 Apr 15;355(Pt 2):499-507. 11284739
  5. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  6. Witter K, Werner T, Blusch JH, Schneider EM, Riess O, Ziegler I, Rodl W, Bacher A, Gutlich M: Cloning, sequencing and functional studies of the gene encoding human GTP cyclohydrolase I. Gene. 1996 Jun 1;171(2):285-90. 8666288
  7. Gutlich M, Schott K, Werner T, Bacher A, Ziegler I: Species and tissue specificity of mammalian GTP cyclohydrolase I messenger RNA. Biochim Biophys Acta. 1992 Dec 29;1171(2):133-40. 1482676
  8. Ichinose H, Ohye T, Matsuda Y, Hori T, Blau N, Burlina A, Rouse B, Matalon R, Fujita K, Nagatsu T: Characterization of mouse and human GTP cyclohydrolase I genes. Mutations in patients with GTP cyclohydrolase I deficiency. J Biol Chem. 1995 Apr 28;270(17):10062-71. 7730309
  9. Blau N, Niederwieser A: The application of 8-aminoguanosine triphosphate, a new inhibitor of GTP cyclohydrolase I, to the purification of the enzyme from human liver. Biochim Biophys Acta. 1986 Jan 15;880(1):26-31. 3753653
  10. Shen RS, Alam A, Zhang YX: Human liver GTP cyclohydrolase I: purification and some properties. Biochimie. 1989 Mar;71(3):343-9. 2500984
  11. Schoedon G, Redweik U, Curtius HC: Purification of GTP cyclohydrolase I from human liver and production of specific monoclonal antibodies. Eur J Biochem. 1989 Jan 2;178(3):627-34. 2463916
  12. Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Schmidt K, Weiss G, Wachter H: Pteridine biosynthesis in human endothelial cells. Impact on nitric oxide-mediated formation of cyclic GMP. J Biol Chem. 1993 Jan 25;268(3):1842-6. 7678411
  13. Thony B, Blau N: Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes. Hum Mutat. 1997;10(1):11-20. 9222755
  14. Katusic ZS, Stelter A, Milstien S: Cytokines stimulate GTP cyclohydrolase I gene expression in cultured human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol. 1998 Jan;18(1):27-32. 9445252
  15. Cai S, Alp NJ, McDonald D, Smith I, Kay J, Canevari L, Heales S, Channon KM: GTP cyclohydrolase I gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells: effects on nitric oxide synthase activity, protein levels and dimerisation. Cardiovasc Res. 2002 Sep;55(4):838-49. 12176133
  16. Ohtsuki M, Shiraishi H, Kato T, Kuroda R, Tazawa M, Sumi-Ichinose C, Tada S, Udagawa Y, Itoh M, Hishida H, Ichinose H, Nagatsu T, Hagino Y, Nomura T: cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells. Life Sci. 2002 Mar 22;70(18):2187-98. 12002810
  17. Gesierich A, Niroomand F, Tiefenbacher CP: Role of human GTP cyclohydrolase I and its regulatory protein in tetrahydrobiopterin metabolism. Basic Res Cardiol. 2003 Mar;98(2):69-75. 12607127
  18. Shiraishi H, Kato T, Atsuta K, Sumi-Ichinose C, Ohtsuki M, Itoh M, Hishida H, Tada S, Udagawa Y, Nagatsu T, Hagino Y, Ichinose H, Nomura T: cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells. J Pharmacol Sci. 2003 Nov;93(3):265-71. 14646243
  19. Suzuki T, Kurita H, Ichinose H: GTP cyclohydrolase I utilizes metal-free GTP as its substrate. Eur J Biochem. 2004 Jan;271(2):349-55. 14717702
  20. Duan CL, Su Y, Zhao CL, Lu LL, Xu QY, Yang H: The assays of activities and function of TH, AADC, and GCH1 and their potential use in ex vivo gene therapy of PD. Brain Res Brain Res Protoc. 2005 Dec;16(1-3):37-43. 16338639
  21. Huang A, Zhang YY, Chen K, Hatakeyama K, Keaney JF Jr: Cytokine-stimulated GTP cyclohydrolase I expression in endothelial cells requires coordinated activation of nuclear factor-kappaB and Stat1/Stat3. Circ Res. 2005 Feb 4;96(2):164-71. Epub 2004 Dec 16. 15604419
  22. Kalivendi S, Hatakeyama K, Whitsett J, Konorev E, Kalyanaraman B, Vasquez-Vivar J: Changes in tetrahydrobiopterin levels in endothelial cells and adult cardiomyocytes induced by LPS and hydrogen peroxide--a role for GFRP? Free Radic Biol Med. 2005 Feb 15;38(4):481-91. 15649650
  23. Pandya MJ, Golderer G, Werner ER, Werner-Felmayer G: Interaction of human GTP cyclohydrolase I with its splice variants. Biochem J. 2006 Nov 15;400(1):75-80. 16848765
  24. Chavan B, Gillbro JM, Rokos H, Schallreuter KU: GTP cyclohydrolase feedback regulatory protein controls cofactor 6-tetrahydrobiopterin synthesis in the cytosol and in the nucleus of epidermal keratinocytes and melanocytes. J Invest Dermatol. 2006 Nov;126(11):2481-9. Epub 2006 Jun 15. 16778797
  25. Swick L, Kapatos G: A yeast 2-hybrid analysis of human GTP cyclohydrolase I protein interactions. J Neurochem. 2006 Jun;97(5):1447-55. 16696853
  26. Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, Ehnert C, Nejim J, Marian C, Scholz J, Wu T, Allchorne A, Diatchenko L, Binshtok AM, Goldman D, Adolph J, Sama S, Atlas SJ, Carlezon WA, Parsegian A, Lotsch J, Fillingim RB, Maixner W, Geisslinger G, Max MB, Woolf CJ: GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006 Nov;12(11):1269-77. Epub 2006 Oct 22. 17057711
  27. Widder JD, Chen W, Li L, Dikalov S, Thony B, Hatakeyama K, Harrison DG: Regulation of tetrahydrobiopterin biosynthesis by shear stress. Circ Res. 2007 Oct 12;101(8):830-8. Epub 2007 Aug 17. 17704208
  28. Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci Signal. 2009 Aug 18;2(84):ra46. doi: 10.1126/scisignal.2000007. 19690332
  29. Auerbach G, Herrmann A, Bracher A, Bader G, Gutlich M, Fischer M, Neukamm M, Garrido-Franco M, Richardson J, Nar H, Huber R, Bacher A: Zinc plays a key role in human and bacterial GTP cyclohydrolase I. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13567-72. 11087827
  30. Ichinose H, Ohye T, Takahashi E, Seki N, Hori T, Segawa M, Nomura Y, Endo K, Tanaka H, Tsuji S, et al.: Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet. 1994 Nov;8(3):236-42. 7874165
  31. Ichinose H, Ohye T, Segawa M, Nomura Y, Endo K, Tanaka H, Tsuji S, Fujita K, Nagatsu T: GTP cyclohydrolase I gene in hereditary progressive dystonia with marked diurnal fluctuation. Neurosci Lett. 1995 Aug 18;196(1-2):5-8. 7501255
  32. Hirano M, Tamaru Y, Ito H, Matsumoto S, Imai T, Ueno S: Mutant GTP cyclohydrolase I mRNA levels contribute to dopa-responsive dystonia onset. Ann Neurol. 1996 Nov;40(5):796-8. 8957022
  33. Bandmann O, Nygaard TG, Surtees R, Marsden CD, Wood NW, Harding AE: Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity. Hum Mol Genet. 1996 Mar;5(3):403-6. 8852666
  34. Beyer K, Lao-Villadoniga JI, Vecino-Bilbao B, Cacabelos R, De la Fuente-Fernandez R: A novel point mutation in the GTP cyclohydrolase I gene in a Spanish family with hereditary progressive and dopa responsive dystonia. J Neurol Neurosurg Psychiatry. 1997 Apr;62(4):420-1. 9120469
  35. Jarman PR, Bandmann O, Marsden CD, Wood NW: GTP cyclohydrolase I mutations in patients with dystonia responsive to anticholinergic drugs. J Neurol Neurosurg Psychiatry. 1997 Sep;63(3):304-8. 9328244
  36. Furukawa Y, Kish SJ, Bebin EM, Jacobson RD, Fryburg JS, Wilson WG, Shimadzu M, Hyland K, Trugman JM: Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations. Ann Neurol. 1998 Jul;44(1):10-6. 9667588
  37. Bandmann O, Valente EM, Holmans P, Surtees RA, Walters JH, Wevers RA, Marsden CD, Wood NW: Dopa-responsive dystonia: a clinical and molecular genetic study. Ann Neurol. 1998 Oct;44(4):649-56. 9778264
  38. Hwu WL, Wang PJ, Hsiao KJ, Wang TR, Chiou YW, Lee YM: Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation. Hum Genet. 1999 Sep;105(3):226-30. 10987649
  39. Suzuki T, Ohye T, Inagaki H, Nagatsu T, Ichinose H: Characterization of wild-type and mutants of recombinant human GTP cyclohydrolase I: relationship to etiology of dopa-responsive dystonia. J Neurochem. 1999 Dec;73(6):2510-6. 10582612
  40. Brique S, Destee A, Lambert JC, Mouroux V, Delacourte A, Amouyel P, Chartier-Harlin MC: A new GTP-cyclohydrolase I mutation in an unusual dopa-responsive dystonia, familial form. Neuroreport. 1999 Feb 25;10(3):487-91. 10208576
  41. Hirano M, Komure O, Ueno S: A novel missense mutant inactivates GTP cyclohydrolase I in dopa-responsive dystonia. Neurosci Lett. 1999 Feb 5;260(3):181-4. 10076897
  42. Tassin J, Durr A, Bonnet AM, Gil R, Vidailhet M, Lucking CB, Goas JY, Durif F, Abada M, Echenne B, Motte J, Lagueny A, Lacomblez L, Jedynak P, Bartholome B, Agid Y, Brice A: Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations? Brain. 2000 Jun;123 ( Pt 6):1112-21. 10825351
  43. Steinberger D, Korinthenberg R, Topka H, Berghauser M, Wedde R, Muller U: Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa. German Dystonia Study Group. Neurology. 2000 Dec 12;55(11):1735-7. 11113234
  44. Leuzzi V, Carducci C, Carducci C, Cardona F, Artiola C, Antonozzi I: Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive myoclonus-dystonia syndrome. Neurology. 2002 Oct 22;59(8):1241-3. 12391354
  45. Ohta E, Funayama M, Ichinose H, Toyoshima I, Urano F, Matsuo M, Tomoko N, Yukihiko K, Yoshino S, Yokoyama H, Shimazu H, Maeda K, Hasegawa K, Obata F: Novel mutations in the guanosine triphosphate cyclohydrolase 1 gene associated with DYT5 dystonia. Arch Neurol. 2006 Nov;63(11):1605-10. 17101830
  46. Cai C, Shi W, Zeng Z, Zhang M, Ling C, Chen L, Cai C, Zhang B, Li WD: GTP cyclohydrolase I and tyrosine hydroxylase gene mutations in familial and sporadic dopa-responsive dystonia patients. PLoS One. 2013 Jun 6;8(6):e65215. doi: 10.1371/journal.pone.0065215. Print 2013. 23762320