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P30793 (GCH1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 155. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
GTP cyclohydrolase 1

EC=3.5.4.16
Alternative name(s):
GTP cyclohydrolase I
Short name=GTP-CH-I
Gene names
Name:GCH1
Synonyms:DYT5, GCH
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length250 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. Ref.2 Ref.16 Ref.17 Ref.22 Ref.28

Catalytic activity

GTP + H2O = formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate. Ref.11 Ref.13 Ref.26

Enzyme regulation

GTP shows a positive allosteric effect, and tetrahydrobiopterin inhibits the enzyme activity. Zinc is required for catalytic activity. Inhibited by Mg2+. Ref.11 Ref.21 Ref.26

Pathway

Cofactor biosynthesis; 7,8-dihydroneopterin triphosphate biosynthesis; 7,8-dihydroneopterin triphosphate from GTP: step 1/1. HAMAP-Rule MF_00223

Subunit structure

Toroid-shaped homodecamer, composed of a dimer of pentamers. The inactive isoforms also form decamers and may possibly be incorporated into GCH1 heterodecamers, decreasing enzyme stability and activity. Interacts with AHSA1 and GCHFR/GFRP. Ref.25 Ref.27 Ref.31

Subcellular location

Cytoplasm. Nucleus Ref.13 Ref.17 Ref.26.

Tissue specificity

In epidermis, expressed predominantly in basal undifferentiated keratinocytes and in some but not all melanocytes (at protein level). Ref.26

Induction

Up-regulated by IFNG/IFN-gamma, TNF, IL1B/interleukin-1 beta, bacterial lipopolysaccharides (LPS) and phenylalanine, and down-regulated by dibutyryl-cAMP, iloprost and 8-bromo-cGMP in HUVEC cells. Up-regulation of GCH1 expression, in turn, stimulates production of tetrahydrobiopterin, with subsequent elevation of endothelial nitric oxide synthase activity. Cytokine-induced GCH1 up-regulation in HUVECs in response to TNF and IFNG/IFN-gamma involves cooperative activation of both the NF-kappa-B and JAK2/STAT pathways. Also up-regulated by hydrogen peroxide in human aorta endothelial cells (HAECs). Ref.11 Ref.14 Ref.16 Ref.18 Ref.19 Ref.20 Ref.21 Ref.23 Ref.24 Ref.26

Post-translational modification

Phosphorylated by casein kinase II at Ser-81 in HAECs during oscillatory shear stress; phosphorylation at Ser-81 results in increased enzyme activity. Ref.29

Involvement in disease

GTP cyclohydrolase 1 deficiency (GCH1D) [MIM:233910]: A cause of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. It is also responsible for defective neurotransmission due to depletion of the neurotransmitters dopamine and serotonin. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing. Some patients may present a phenotype of intermediate severity between severe hyperphenylalaninemia and mild dystonia type 5 (dystonia-parkinsonism with diurnal fluctuation). In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.33 Ref.38

Dystonia 5 (DYT5) [MIM:128230]: A DOPA-responsive dystonia. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT5 typically presents in childhood with walking problems due to dystonia of the lower limbs and worsening of the dystonia towards the evening. It is characterized by postural and motor disturbances showing marked diurnal fluctuation. Torsion of the trunk is unusual. Symptoms are alleviated after sleep and aggravated by fatigue and exercise. There is a favorable response to L-DOPA without side effects.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.32 Ref.33 Ref.34 Ref.35 Ref.36 Ref.37 Ref.39 Ref.40 Ref.41 Ref.42 Ref.43 Ref.44 Ref.45 Ref.46 Ref.47

Sequence similarities

Belongs to the GTP cyclohydrolase I family.

Biophysicochemical properties

Kinetic parameters:

KM=116 µM for GTP Ref.12

pH dependence:

Optimum pH is 7.7 in phosphate buffer.

Temperature dependence:

Relatively stable at high temperatures. Retains 50% of its activity after incubation at 70 degrees Celsius for 15 minutes.

Ontologies

Keywords
   Biological processTetrahydrobiopterin biosynthesis
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
Dystonia
Parkinsonism
Phenylketonuria
   LigandGTP-binding
Metal-binding
Nucleotide-binding
Zinc
   Molecular functionHydrolase
   PTMPhosphoprotein
   Technical term3D-structure
Allosteric enzyme
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_process7,8-dihydroneopterin 3'-triphosphate biosynthetic process

Inferred from electronic annotation. Source: UniProtKB-UniPathway

GTP catabolic process

Inferred from direct assay Ref.13. Source: UniProtKB

dopamine biosynthetic process

Inferred from direct assay Ref.22. Source: UniProtKB

metabolic process

Inferred from direct assay Ref.11. Source: GOC

negative regulation of blood pressure

Inferred from electronic annotation. Source: Ensembl

neuromuscular process controlling posture

Inferred from mutant phenotype Ref.32. Source: MGI

nitric oxide biosynthetic process

Non-traceable author statement Ref.16. Source: UniProtKB

nitric oxide metabolic process

Traceable author statement. Source: Reactome

positive regulation of nitric-oxide synthase activity

Inferred from direct assay Ref.17PubMed 15721862. Source: UniProtKB

protein heterooligomerization

Inferred from electronic annotation. Source: Ensembl

protein homooligomerization

Inferred from direct assay PubMed 11087823. Source: UniProtKB

pteridine-containing compound biosynthetic process

Inferred from direct assay PubMed 15721862Ref.13Ref.11. Source: UniProtKB

regulation of blood pressure

Inferred from mutant phenotype PubMed 17717598. Source: UniProtKB

regulation of lung blood pressure

Inferred from electronic annotation. Source: Ensembl

regulation of nitric-oxide synthase activity

Traceable author statement. Source: Reactome

response to interferon-gamma

Inferred from direct assay Ref.19Ref.14Ref.16. Source: UniProtKB

response to lipopolysaccharide

Inferred from direct assay Ref.14Ref.16. Source: UniProtKB

response to pain

Inferred from sequence or structural similarity. Source: UniProtKB

response to tumor necrosis factor

Inferred from direct assay Ref.16. Source: UniProtKB

small molecule metabolic process

Traceable author statement. Source: Reactome

tetrahydrobiopterin biosynthetic process

Inferred from direct assay Ref.14Ref.16. Source: UniProtKB

tetrahydrofolate biosynthetic process

Inferred from electronic annotation. Source: InterPro

vasodilation

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcytoplasm

Inferred from direct assay PubMed 10907721. Source: UniProtKB

cytoplasmic vesicle

Inferred from direct assay PubMed 3318829. Source: UniProtKB

cytosol

Inferred from direct assay Ref.13PubMed 3318829. Source: UniProtKB

nuclear membrane

Inferred from direct assay. Source: HPA

nucleus

Inferred from direct assay Ref.26. Source: UniProtKB

protein complex

Inferred from direct assay PubMed 11087823. Source: UniProtKB

   Molecular_functionGTP binding

Inferred from direct assay Ref.21Ref.11. Source: UniProtKB

GTP cyclohydrolase I activity

Inferred from direct assay Ref.26Ref.11. Source: UniProtKB

calcium ion binding

Inferred from electronic annotation. Source: Ensembl

coenzyme binding

Inferred from electronic annotation. Source: Ensembl

protein homodimerization activity

Inferred from physical interaction PubMed 1669853. Source: UniProtKB

zinc ion binding

Inferred from direct assay PubMed 11087823Ref.21. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

AHSA1O954333EBI-958183,EBI-448610
YWHAZP631044EBI-958183,EBI-347088

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]
Isoform GCH-1 (identifier: P30793-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform GCH-2 (identifier: P30793-2)

The sequence of this isoform differs from the canonical sequence as follows:
     210-213: HMCM → SAEP
     214-250: Missing.
Isoform GCH-3 (identifier: P30793-3)

The sequence of this isoform differs from the canonical sequence as follows:
     210-250: Missing.
Isoform GCH-4 (identifier: P30793-4)

The sequence of this isoform differs from the canonical sequence as follows:
     210-233: HMCMVMRGVQKMNSKTVTSTMLGV → KSNKYNKGLSPLLSSCHLFVAILK
     234-250: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 250250GTP cyclohydrolase 1 HAMAP-Rule MF_00223
PRO_0000119478

Sites

Metal binding1411Zinc
Metal binding1441Zinc
Metal binding2121Zinc

Amino acid modifications

Modified residue601Phosphoserine Ref.30
Modified residue811Phosphoserine Ref.29

Natural variations

Alternative sequence210 – 25041Missing in isoform GCH-3.
VSP_001610
Alternative sequence210 – 23324HMCMV…TMLGV → KSNKYNKGLSPLLSSCHLFV AILK in isoform GCH-4.
VSP_001611
Alternative sequence210 – 2134HMCM → SAEP in isoform GCH-2.
VSP_001612
Alternative sequence214 – 25037Missing in isoform GCH-2.
VSP_001613
Alternative sequence234 – 25017Missing in isoform GCH-4.
VSP_001614
Natural variant151G → D in HGCH-3.
VAR_002632
Natural variant231P → L in DYT5. Ref.37
Corresponds to variant rs41298432 [ dbSNP | Ensembl ].
VAR_002633
Natural variant711L → Q in DYT5. Ref.39
VAR_016888
Natural variant741A → V in DYT5. Ref.39
VAR_016889
Natural variant791L → P in DYT5. Ref.33
VAR_002634
Natural variant831G → A in DYT5. Ref.39 Ref.44
VAR_016890
Natural variant88 – 892Missing in DYT5.
VAR_016891
Natural variant881R → P in DYT5. Ref.35
VAR_002635
Natural variant881R → W in DYT5. Ref.32
VAR_002636
Natural variant901G → V in DYT5. Ref.43
VAR_016892
Natural variant1021M → K in DYT5. Ref.41
VAR_002637
Natural variant1021M → R in DYT5. Ref.41
VAR_016893
Natural variant1061T → I in DYT5. Ref.47
VAR_054112
Natural variant1081G → D in GCH1D; phenotype presenting with dystonia and motor delay. Ref.38
VAR_016894
Natural variant1151D → N in DYT5. Ref.37
VAR_016895
Natural variant1341D → V in DYT5. Ref.32
VAR_002638
Natural variant1351I → K in DYT5. Ref.42
VAR_016896
Natural variant1411C → R in DYT5. Ref.41
VAR_016897
Natural variant1411C → W in DYT5. Ref.41
VAR_002639
Natural variant1441H → P in DYT5. Ref.34
VAR_002640
Natural variant1531H → P in DYT5. Ref.35
VAR_002641
Natural variant1631L → R in DYT5. Ref.45
VAR_016898
Natural variant1761S → T in DYT5. Ref.41
VAR_016899
Natural variant1781R → S in DYT5. Ref.36 Ref.41 Ref.44
VAR_002642
Natural variant1801Q → R in DYT5. Ref.44
VAR_016900
Natural variant1841R → H in GCH1D; severe hyperphenylalaninemia. Ref.33
VAR_002643
Natural variant1861T → K in DYT5. Ref.41
VAR_002644
Natural variant1911V → I in DYT5. Ref.39
VAR_016901
Natural variant1991P → L in DYT5. Ref.44
VAR_016902
Natural variant2011G → E in DYT5. Ref.32 Ref.44
VAR_002645
Natural variant2031G → R in DYT5. Ref.35
VAR_002646
Natural variant2111M → I in GCH1D; severe hyperphenylalaninemia. Ref.33
VAR_002647
Natural variant2111M → V in DYT5. Ref.39
VAR_016903
Natural variant2131M → V in DYT5. Ref.45
VAR_016904
Natural variant2211M → T in GCH1D; a patient presenting with dystonia and motor delay; compound heterozygote for an additional deletion. Ref.38
VAR_016905
Natural variant2241K → R in GCH1D and DYT5; phenotype presenting with dystonia and myoclonus. Ref.35 Ref.38 Ref.46
Corresponds to variant rs41298442 [ dbSNP | Ensembl ].
VAR_002648
Natural variant2341F → S in DYT5. Ref.35
VAR_002649
Natural variant2411R → W in DYT5. Ref.39
VAR_016906
Natural variant2491R → S in DYT5. Ref.40
VAR_016907

Experimental info

Sequence conflict111E → G in AAD38866. Ref.4
Sequence conflict2061V → I in CAA78908. Ref.9

Secondary structure

............................... 250
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform GCH-1 [UniParc].

Last modified July 1, 1993. Version 1.
Checksum: B8A0CB344C598B9A

FASTA25027,903
        10         20         30         40         50         60 
MEKGPVRAPA EKPRGARCSN GFPERDPPRP GPSRPAEKPP RPEAKSAQPA DGWKGERPRS 

        70         80         90        100        110        120 
EEDNELNLPN LAAAYSSILS SLGENPQRQG LLKTPWRAAS AMQFFTKGYQ ETISDVLNDA 

       130        140        150        160        170        180 
IFDEDHDEMV IVKDIDMFSM CEHHLVPFVG KVHIGYLPNK QVLGLSKLAR IVEIYSRRLQ 

       190        200        210        220        230        240 
VQERLTKQIA VAITEALRPA GVGVVVEATH MCMVMRGVQK MNSKTVTSTM LGVFREDPKT 

       250 
REEFLTLIRS 

« Hide

Isoform GCH-2 [UniParc].

Checksum: 021D95DE6B33E02A
Show »

FASTA21323,516
Isoform GCH-3 [UniParc].

Checksum: 8B33E02A53DF1259
Show »

FASTA20923,131
Isoform GCH-4 [UniParc].

Checksum: 7100FBD83BFDB2C9
Show »

FASTA23325,775

References

« Hide 'large scale' references
[1]"Multiple mRNA forms of human GTP cyclohydrolase I."
Togari A., Ichinose H., Matsumoto S., Fujita K., Nagatsu T.
Biochem. Biophys. Res. Commun. 187:359-365(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS GCH-1; GCH-2 AND GCH-3).
Tissue: Liver.
[2]"Human GTP cyclohydrolase I: only one out of three cDNA isoforms gives rise to the active enzyme."
Guetlich M., Jaeger E., Rucknaegel K.P., Werner T., Roedl W., Ziegler I., Bacher A.
Biochem. J. 302:215-221(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS GCH-1 AND GCH-2), FUNCTION.
Tissue: Liver.
[3]"Isolation of a full-length cDNA clone for human GTP cyclohydrolase I type 1 from pheochromocytoma."
Nomura T., Ohtsuki M., Matsui S., Sumi-Ichinose C., Nomura H., Hagino Y., Iwase K., Ichinose H., Fujita K., Nagatsu T.
J. Neural Transm. 101:237-242(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Pheochromocytoma.
[4]"GTP cyclohydrolase I mRNA: novel splice variants in the slime mould Physarum polycephalum and in human monocytes (THP-1) indicate conservation of mRNA processing."
Golderer G., Werner E.R., Heufler C., Strohmaier W., Grobner P., Werner-Felmayer G.
Biochem. J. 355:499-507(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS GCH-1 AND GCH-4).
Tissue: Myelomonocyte.
[5]"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)."
Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.
Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM GCH-1).
[6]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM GCH-1).
Tissue: Brain.
[8]"Cloning, sequencing and functional studies of the gene encoding human GTP cyclohydrolase I."
Witter K., Werner T., Blusch J.H., Schneider E.-M., Riess O., Ziegler I., Roedl W., Bacher A., Guetlich M.
Gene 171:285-290(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-114.
Tissue: Granulocyte.
[9]"Species and tissue specificity of mammalian GTP cyclohydrolase I messenger RNA."
Guetlich M., Schott K., Werner T., Bacher A., Ziegler I.
Biochim. Biophys. Acta 1171:133-140(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 60-242.
[10]"Characterization of mouse and human GTP cyclohydrolase I genes. Mutations in patients with GTP cyclohydrolase I deficiency."
Ichinose H., Ohye T., Matsuda Y., Hori T.A., Blau N., Burlina A., Rouse B., Matalon R., Fujita K., Nagatsu T.
J. Biol. Chem. 270:10062-10071(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 116-209.
[11]"The application of 8-aminoguanosine triphosphate, a new inhibitor of GTP cyclohydrolase I, to the purification of the enzyme from human liver."
Blau N., Niederwieser A.
Biochim. Biophys. Acta 880:26-31(1986) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME ACTIVITY, ENZYME REGULATION.
[12]"Human liver GTP cyclohydrolase I: purification and some properties."
Shen R.-S., Alam A., Zhang Y.X.
Biochimie 71:343-349(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: BIOPHYSICOCHEMICAL PROPERTIES.
[13]"Purification of GTP cyclohydrolase I from human liver and production of specific monoclonal antibodies."
Schoedon G., Redweik U., Curtius H.-C.
Eur. J. Biochem. 178:627-634(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME ACTIVITY, SUBCELLULAR LOCATION.
[14]"Pteridine biosynthesis in human endothelial cells. Impact on nitric oxide-mediated formation of cyclic GMP."
Werner-Felmayer G., Werner E.R., Fuchs D., Hausen A., Reibnegger G., Schmidt K., Weiss G., Wachter H.
J. Biol. Chem. 268:1842-1846(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION.
[15]"Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes."
Thoeny B., Blau N.
Hum. Mutat. 10:11-20(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON VARIANTS.
[16]"Cytokines stimulate GTP cyclohydrolase I gene expression in cultured human umbilical vein endothelial cells."
Katusic Z.S., Stelter A., Milstien S.
Arterioscler. Thromb. Vasc. Biol. 18:27-32(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION.
[17]"GTP cyclohydrolase I gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells: effects on nitric oxide synthase activity, protein levels and dimerisation."
Cai S., Alp N.J., McDonald D., Smith I., Kay J., Canevari L., Heales S., Channon K.M.
Cardiovasc. Res. 55:838-849(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[18]"cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells."
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.
Life Sci. 70:2187-2198(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION.
[19]"Role of human GTP cyclohydrolase I and its regulatory protein in tetrahydrobiopterin metabolism."
Gesierich A., Niroomand F., Tiefenbacher C.P.
Basic Res. Cardiol. 98:69-75(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION.
[20]"cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells."
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.
J. Pharmacol. Sci. 93:265-271(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION.
[21]"GTP cyclohydrolase I utilizes metal-free GTP as its substrate."
Suzuki T., Kurita H., Ichinose H.
Eur. J. Biochem. 271:349-355(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION.
[22]"The assays of activities and function of TH, AADC, and GCH1 and their potential use in ex vivo gene therapy of PD."
Duan C.-L., Su Y., Zhao C.-L., Lu L.-L., Xu Q.-Y., Yang H.
Brain Res. Brain Res. Protoc. 16:37-43(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[23]"Cytokine-stimulated GTP cyclohydrolase I expression in endothelial cells requires coordinated activation of nuclear factor-kappaB and Stat1/Stat3."
Huang A., Zhang Y.-Y., Chen K., Hatakeyama K., Keaney J.F. Jr.
Circ. Res. 96:164-171(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION.
[24]"Changes in tetrahydrobiopterin levels in endothelial cells and adult cardiomyocytes induced by LPS and hydrogen peroxide -- a role for GFRP?"
Kalivendi S., Hatakeyama K., Whitsett J., Konorev E., Kalyanaraman B., Vasquez-Vivar J.
Free Radic. Biol. Med. 38:481-491(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION.
[25]"Interaction of human GTP cyclohydrolase I with its splice variants."
Pandya M.J., Golderer G., Werner E.R., Werner-Felmayer G.
Biochem. J. 400:75-80(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBUNIT.
[26]"GTP cyclohydrolase feedback regulatory protein controls cofactor 6-tetrahydrobiopterin synthesis in the cytosol and in the nucleus of epidermal keratinocytes and melanocytes."
Chavan B., Gillbro J.M., Rokos H., Schallreuter K.U.
J. Invest. Dermatol. 126:2481-2489(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME ACTIVITY, ENZYME REGULATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[27]"A yeast 2-hybrid analysis of human GTP cyclohydrolase I protein interactions."
Swick L., Kapatos G.
J. Neurochem. 97:1447-1455(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AHSA1 AND GCHFR.
[28]"GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence."
Tegeder I., Costigan M., Griffin R.S., Abele A., Belfer I., Schmidt H., Ehnert C., Nejim J., Marian C., Scholz J., Wu T., Allchorne A., Diatchenko L., Binshtok A.M., Goldman D., Adolph J., Sama S., Atlas S.J. expand/collapse author list , Carlezon W.A., Parsegian A., Loetsch J., Fillingim R.B., Maixner W., Geisslinger G., Max M.B., Woolf C.J.
Nat. Med. 12:1269-1277(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[29]"Regulation of tetrahydrobiopterin biosynthesis by shear stress."
Widder J.D., Chen W., Li L., Dikalov S., Thony B., Hatakeyama K., Harrison D.G.
Circ. Res. 101:830-838(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-81.
[30]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-60, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[31]"Zinc plays a key role in human and bacterial GTP cyclohydrolase I."
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.
Proc. Natl. Acad. Sci. U.S.A. 97:13567-13572(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 55-250, SUBUNIT, ZINC-BINDING SITES.
[32]"Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene."
Ichinose H., Ohye T., Takahashi E., Seki N., Hori T., Segawa M., Nomura Y., Endo K., Tanaka H., Tsuji S., Fujita K., Nagatsu T.
Nat. Genet. 8:236-242(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS DYT5 TRP-88; VAL-134 AND GLU-201.
[33]"GTP cyclohydrolase I gene in hereditary progressive dystonia with marked diurnal fluctuation."
Ichinose H., Ohye T., Segawa M., Nomura Y., Endo K., Tanaka H., Tsuji S., Fujita K., Nagatsu T.
Neurosci. Lett. 196:5-8(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT DYT5 PRO-79, VARIANTS GCH1D HIS-184 AND ILE-211.
[34]"Mutant GTP cyclohydrolase I mRNA levels contribute to dopa-responsive dystonia onset."
Hirano M., Tamaru Y., Ito H., Matsumoto S., Imai T., Ueno S.
Ann. Neurol. 40:796-798(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT DYT5 PRO-144.
[35]"Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity."
Bandmann O., Nygaard T.G., Surtess R., Mardsen C.D., Wood N.W., Harding A.E.
Hum. Mol. Genet. 5:403-406(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS DYT5 PRO-88; PRO-153; ARG-203; ARG-224 AND SER-234.
[36]"A novel point mutation in the GTP cyclohydrolase I gene in a Spanish family with hereditary progressive and dopa responsive dystonia."
Beyer K., Lao-Villadoniga J.I., Vecino-Bilbao B., Cacabelos R., de la Fuent-Fernandez R.
J. Neurol. Neurosurg. Psych. 62:420-421(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT DYT5 SER-178.
[37]"GTP cyclohydrolase I mutations in patients with dystonia responsive to anticholinergic drugs."
Jarman P.R., Bandmann O., Marsden C.D., Wood N.W.
J. Neurol. Neurosurg. Psych. 63:304-308(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS DYT5 LEU-23 AND ASN-115.
[38]"Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations."
Furukawa Y., Kish S.J., Bebin E.M., Jacobson R.D., Fryburg J.S., Wilson W.G., Shimadzu M., Hyland K., Trugman J.M.
Ann. Neurol. 44:10-16(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS GCH1D ASP-108; THR-221 AND ARG-224.
[39]"Dopa-responsive dystonia: a clinical and molecular genetic study."
Bandmann O., Valente E.M., Holmans P., Surtees R.A., Walters J.H., Wevers R.A., Marsden C.D., Wood N.W.
Ann. Neurol. 44:649-656(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS DYT5 GLN-71; VAL-74; ALA-83; ILE-191; VAL-211 AND TRP-241.
[40]"Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation."
Hwu W.-L., Wang P.-J., Hsiao K.-J., Wang T.-R., Chiou Y.-W., Lee Y.-M.
Hum. Genet. 105:226-230(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT DYT5 SER-249.
[41]"Characterization of wild-type and mutants of recombinant human GTP cyclohydrolase I: relationship to etiology of dopa-responsive dystonia."
Suzuki T., Ohye T., Inagaki H., Nagatsu T., Ichinose H.
J. Neurochem. 73:2510-2516(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS DYT5 ARG-102; LYS-102; ARG-141; TRP-141; THR-176; SER-178 AND LYS-186.
[42]"A new GTP-cyclohydrolase I mutation in an unusual dopa-responsive dystonia, familial form."
Brique S., Destee A., Lambert J.-C., Mouroux V., Delacourte A., Amouyel P., Chartier-Harlin M.-C.
NeuroReport 10:487-491(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT DYT5 LYS-135.
[43]"A novel missense mutant inactivates GTP cyclohydrolase I in dopa-responsive dystonia."
Hirano M., Komure O., Ueno S.
Neurosci. Lett. 260:181-184(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT DYT5 VAL-90.
[44]"Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations?"
Tassin J., Duerr A., Bonnet A.-M., Gil R., Vidailhet M., Luecking C.B., Goas J.-Y., Durif F., Abada M., Echenne B., Motte J., Lagueny A., Lacomblez L., Jedynak P., Bartholome B., Agid Y., Brice A.
Brain 123:1112-1121(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS DYT5 ALA-83; 88-ARG-GLN-89 DEL; SER-178; ARG-180; LEU-199 AND GLU-201.
[45]"Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa. German Dystonia Study Group."
Steinberger D., Korinthenberg R., Topka H., Berghaeuser M., Wedde R., Mueller U.
Neurology 55:1735-1737(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS DYT5 ARG-163 AND VAL-213.
[46]"Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive myoclonus-dystonia syndrome."
Leuzzi V., Carducci C., Carducci C., Cardona F., Artiola C., Antonozzi I.
Neurology 59:1241-1243(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT DYT5 ARG-224.
[47]"Novel mutations in the guanosine triphosphate cyclohydrolase 1 gene associated with DYT5 dystonia."
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.
Arch. Neurol. 63:1605-1610(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT DYT5 ILE-106.
+Additional computationally mapped references.

Web resources

BIOMDB

Db of mutations causing tetrahydrobiopterin deficiencies

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
S44049 mRNA. Translation: AAB23164.1.
S44053 mRNA. Translation: AAB23165.1.
S43856 mRNA. Translation: AAB23166.1.
Z29433 mRNA. Translation: CAB77391.1.
Z29434 mRNA. Translation: CAB77392.1.
U19523 mRNA. Translation: AAB16861.1.
U66095 mRNA. Translation: AAD38866.1.
U66097 mRNA. Translation: AAD38868.1.
CR536551 mRNA. Translation: CAG38788.1.
CH471061 Genomic DNA. Translation: EAW80647.1.
BC025415 mRNA. Translation: AAH25415.1.
L29478 Genomic DNA. Translation: AAB42186.1.
Z30952 Genomic DNA. Translation: CAA83213.1.
Z16418 mRNA. Translation: CAA78908.1.
U19259 expand/collapse EMBL AC list , U19256, U19257, U19258 Genomic DNA. Translation: AAB60633.1.
PIRPC1117. G01630.
JC1225.
RefSeqNP_000152.1. NM_000161.2.
NP_001019195.1. NM_001024024.1.
NP_001019241.1. NM_001024070.1.
NP_001019242.1. NM_001024071.1.
XP_005267587.1. XM_005267530.1.
UniGeneHs.86724.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1FB1X-ray3.10A/B/C/D/E55-250[»]
ProteinModelPortalP30793.
SMRP30793. Positions 55-250.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108913. 30 interactions.
IntActP30793. 12 interactions.
MINTMINT-3011998.
STRING9606.ENSP00000378890.

PTM databases

PhosphoSiteP30793.

Polymorphism databases

DMDM399536.

Proteomic databases

PaxDbP30793.
PRIDEP30793.

Protocols and materials databases

DNASU2643.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000395514; ENSP00000378890; ENSG00000131979. [P30793-1]
ENST00000491895; ENSP00000419045; ENSG00000131979. [P30793-1]
ENST00000536224; ENSP00000445246; ENSG00000131979. [P30793-2]
ENST00000543643; ENSP00000444011; ENSG00000131979. [P30793-4]
GeneID2643.
KEGGhsa:2643.
UCSCuc001xbh.1. human. [P30793-1]
uc001xbj.1. human. [P30793-4]
uc001xbk.1. human. [P30793-2]

Organism-specific databases

CTD2643.
GeneCardsGC14M055308.
HGNCHGNC:4193. GCH1.
HPAHPA028612.
MIM128230. phenotype.
233910. phenotype.
600225. gene.
neXtProtNX_P30793.
Orphanet98808. Autosomal dominant dopa-responsive dystonia.
2102. GTP cyclohydrolase I deficiency.
PharmGKBPA28608.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0302.
HOGENOMHOG000221222.
HOVERGENHBG003136.
InParanoidP30793.
KOK01495.
OMAVIVVTEC.
OrthoDBEOG77DJ6T.
PhylomeDBP30793.
TreeFamTF105616.

Enzyme and pathway databases

BioCycMetaCyc:HS05586-MONOMER.
ReactomeREACT_111217. Metabolism.
SABIO-RKP30793.
UniPathwayUPA00848; UER00151.

Gene expression databases

ArrayExpressP30793.
BgeeP30793.
CleanExHS_GCH1.
GenevestigatorP30793.

Family and domain databases

HAMAPMF_00223. FolE.
InterProIPR001474. GTP_CycHdrlase_I.
IPR018234. GTP_CycHdrlase_I_CS.
IPR020602. GTP_CycHdrlase_I_dom.
[Graphical view]
PANTHERPTHR11109. PTHR11109. 1 hit.
PfamPF01227. GTP_cyclohydroI. 1 hit.
[Graphical view]
TIGRFAMsTIGR00063. folE. 1 hit.
PROSITEPS00859. GTP_CYCLOHYDROL_1_1. 1 hit.
PS00860. GTP_CYCLOHYDROL_1_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP30793.
GeneWikiGTP_cyclohydrolase_I.
GenomeRNAi2643.
NextBio10420.
PROP30793.
SOURCESearch...

Entry information

Entry nameGCH1_HUMAN
AccessionPrimary (citable) accession number: P30793
Secondary accession number(s): Q6FHY7, Q9Y4I8
Entry history
Integrated into UniProtKB/Swiss-Prot: July 1, 1993
Last sequence update: July 1, 1993
Last modified: April 16, 2014
This is version 155 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 14

Human chromosome 14: entries, gene names and cross-references to MIM