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Identification
HMDB Protein ID HMDBP00938
Secondary Accession Numbers
  • 6226
  • HMDBP05047
Name GTP cyclohydrolase 1
Synonyms
  1. GTP cyclohydrolase I
  2. GTP-CH-I
Gene Name GCH1
Protein Type Unknown
Biological Properties
General Function Involved in GTP cyclohydrolase I activity
Specific Function Positively 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.
Pathways
  • 7,8-dihydroneopterin triphosphate biosynthesis
  • Dopa-responsive dystonia
  • Folate biosynthesis
  • Hyperphenylalaniemia due to guanosine triphosphate cyclohydrolase deficiency
  • Hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency (ptps)
  • Hyperphenylalaninemia due to dhpr-deficiency
  • Pterine Biosynthesis
  • Segawa syndrome
  • Sepiapterin reductase deficiency
Reactions
Guanosine triphosphate + Water → Formic acid + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate details
Guanosine triphosphate + Water → Formamidopyrimidine nucleoside triphosphate details
Dihydroneopterin triphosphate + Water → 2,5-Diamino-6-(5'-triphosphoryl-3',4'-trihydroxy-2'-oxopentyl)-amino-4-oxopyrimidine details
Formamidopyrimidine nucleoside triphosphate + Water → 2,5-Diaminopyrimidine nucleoside triphosphate + Formic acid details
2,5-Diaminopyrimidine nucleoside triphosphate → 2,5-Diamino-6-(5'-triphosphoryl-3',4'-trihydroxy-2'-oxopentyl)-amino-4-oxopyrimidine details
GO Classification
Biological Process
response to pain
GTP catabolic process
dopamine biosynthetic process
response to lipopolysaccharide
vasodilation
negative regulation of blood pressure
induction of apoptosis
response to interferon-gamma
response to tumor necrosis factor
7,8-dihydroneopterin 3'-triphosphate biosynthetic process
neuromuscular process controlling posture
positive regulation of nitric-oxide synthase activity
protein heterooligomerization
regulation of lung blood pressure
protein homooligomerization
regulation of blood pressure
tetrahydrobiopterin biosynthetic process
nitric oxide biosynthetic process
tetrahydrofolate biosynthetic process
Cellular Component
cytosol
nuclear membrane
cytoplasmic vesicle
protein complex
Component
cell part
intracellular part
cytoplasm
Function
catalytic activity
hydrolase activity
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds
cyclohydrolase activity
gtp cyclohydrolase activity
gtp cyclohydrolase i activity
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amidines
Molecular Function
zinc ion binding
GTP cyclohydrolase I activity
calcium ion binding
GTP binding
coenzyme binding
Process
metabolic process
cellular aromatic compound metabolic process
folic acid and derivative metabolic process
tetrahydrofolate biosynthetic process
cellular metabolic process
folic acid and derivative biosynthetic process
Cellular Location
  1. Nucleus
  2. Cytoplasm
Gene Properties
Chromosome Location 14
Locus 14q22.1-q22.2
SNPs GCH1
Gene Sequence
>753 bp
ATGGAGAAGGGCCCTGTGCGGGCACCGGCGGAGAAGCCGCGGGGCGCCAGGTGCAGCAAT
GGGTTCCCCGAGCGGGATCCGCCGCGGCCCGGGCCCAGCAGGCCGGCGGAGAAGCCCCCG
CGGCCCGAGGCCAAGAGCGCGCAGCCCGCGGACGGCTGGAAGGGCGAGCGGCCCCGCAGC
GAGGAGGATAACGAGCTGAACCTCCCTAACCTGGCAGCCGCCTACTCGTCCATCCTGAGC
TCGCTGGGCGAGAACCCCCAGCGGCAAGGGCTGCTCAAGACGCCCTGGAGGGCGGCCTCG
GCCATGCAGTTCTTCACCAAGGGCTACCAGGAGACCATCTCAGATGTCCTAAACGATGCT
ATATTTGATGAAGATCATGATGAGATGGTGATTGTGAAGGACATAGACATGTTTTCCATG
TGTGAGCATCACTTGGTTCCATTTGTTGGAAAGGTCCATATTGGTTATCTTCCTAACAAG
CAAGTCCTTGGCCTCAGCAAACTTGCGAGGATTGTAGAAATCTATAGTAGAAGACTACAA
GTTCAGGAGCGCCTTACAAAACAAATTGCTGTAGCAATCACGGAAGCCTTGCGGCCTGCT
GGAGTCGGGGTAGTGGTTGAAGCAACACACATGTGTATGGTAATGCGAGGTGTACAGAAA
ATGAACAGCAAAACTGTGACCAGCACAATGTTGGGTGTGTTCCGGGAGGATCCAAAGACT
CGGGAAGAGTTCCTGACTCTCATTAGGAGCTGA
Protein Properties
Number of Residues 250
Molecular Weight 27902.855
Theoretical pI 8.556
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence
>GTP cyclohydrolase 1
MEKGPVRAPAEKPRGARCSNGFPERDPPRPGPSRPAEKPPRPEAKSAQPADGWKGERPRS
EEDNELNLPNLAAAYSSILSSLGENPQRQGLLKTPWRAASAMQFFTKGYQETISDVLNDA
IFDEDHDEMVIVKDIDMFSMCEHHLVPFVGKVHIGYLPNKQVLGLSKLARIVEIYSRRLQ
VQERLTKQIAVAITEALRPAGVGVVVEATHMCMVMRGVQKMNSKTVTSTMLGVFREDPKT
REEFLTLIRS
GenBank ID Protein 19343964
UniProtKB/Swiss-Prot ID P30793
UniProtKB/Swiss-Prot Entry Name GCH1_HUMAN
PDB IDs
GenBank Gene ID BC025415
GeneCard ID GCH1
GenAtlas ID GCH1
HGNC ID HGNC:4193
References
General References
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  4. 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. [PubMed:1520321 ]
  5. 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. [PubMed:8068008 ]
  6. 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. [PubMed:8695054 ]
  7. 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. [PubMed:11284739 ]
  8. 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. [PubMed:8666288 ]
  9. 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. [PubMed:1482676 ]
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  11. 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. [PubMed:3753653 ]
  12. Shen RS, Alam A, Zhang YX: Human liver GTP cyclohydrolase I: purification and some properties. Biochimie. 1989 Mar;71(3):343-9. [PubMed:2500984 ]
  13. 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. [PubMed:2463916 ]
  14. 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. [PubMed:7678411 ]
  15. 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. [PubMed:9445252 ]
  16. 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. [PubMed:12176133 ]
  17. 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. [PubMed:12002810 ]
  18. 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. [PubMed:12607127 ]
  19. 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. [PubMed:14646243 ]
  20. 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. [PubMed:14717702 ]
  21. 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. [PubMed:16338639 ]
  22. 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. [PubMed:15604419 ]
  23. 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. [PubMed:15649650 ]
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  25. 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. [PubMed:16778797 ]
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  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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed:9120469 ]
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  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. [PubMed: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. [PubMed: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. [PubMed:10825351 ]
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  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. [PubMed: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. [PubMed:17101830 ]