Reviewed, UniProtKB/Swiss-Prot P30793 (GCH1_HUMAN)

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	250 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence 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.14 Ref.15 Ref.20 Ref.26
Catalytic activity	GTP + H2O = formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate. Ref.9 Ref.11 Ref.24
Enzyme regulation	GTP shows a positive allosteric effect, and tetrahydrobiopterin inhibits the enzyme activity. Zinc is required for catalytic activity. Inhibited by Mg2+. Ref.9 Ref.24 Ref.19
Pathway	Cofactor biosynthesis; 7,8-dihydroneopterin triphosphate biosynthesis; 7,8-dihydroneopterin triphosphate from GTP: step 1/1.
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.23 Ref.25 Ref.28
Subcellular location	Cytoplasm. Nucleus. Ref.15 Ref.11 Ref.24
Tissue specificity	In epidermis, expressed predominantly in basal undifferentiated keratinocytes and in some but not all melanocytes (at protein level). Ref.24
Induction	Up-regulated by interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin 1-beta (IL-beta), lipopolysaccharide (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-alpha and 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.14 Ref.12 Ref.16 Ref.17 Ref.18 Ref.21 Ref.22
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.27
Involvement in disease	Defects in GCH1 are the cause of GTP cyclohydrolase 1 deficiency (GCH1D) [MIM:233910]; also known as atypical severe phenylketonuria due to GTP cyclohydrolase I deficiency;. GCH1D is one of the causes 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. Ref.30 Ref.35 Defects in GCH1 are the cause of dystonia type 5 (DYT5) [MIM:128230]; also known as progressive dystonia with diurnal fluctuation, autosomal dominant Segawa syndrome or dystonia-parkinsonism with diurnal fluctuation. DYT5 is 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 excercise. There is a favorable response to L-DOPA without side effects. Ref.30 Ref.29 Ref.31 Ref.32 Ref.33 Ref.34 Ref.36 Ref.37 Ref.38 Ref.39 Ref.40 Ref.41 Ref.42 Ref.43 Ref.44
Sequence similarities	Belongs to the GTP cyclohydrolase I family.
Biophysicochemical properties	Kinetic parameters: KM=116 µM for GTP 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 process	Tetrahydrobiopterin biosynthesis
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Dystonia Parkinsonism Phenylketonuria
Ligand	GTP-binding Metal-binding Nucleotide-binding Zinc
Molecular function	Hydrolase
PTM	Phosphoprotein
Technical term	3D-structure Allosteric enzyme Complete proteome
Gene Ontology (GO)
Biological process	GTP catabolic process Ref.11 Inferred from direct assay. Source: UniProtKB dopamine biosynthetic process Ref.20 Inferred from direct assay. Source: UniProtKB neuromuscular process controlling posture Ref.29 Inferred from mutant phenotype. Source: MGI nitric oxide biosynthetic process Ref.14 Non-traceable author statement. Source: UniProtKB positive regulation of nitric-oxide synthase activity Ref.15 Inferred from direct assay. Source: UniProtKB protein homooligomerization Inferred from direct assay. Source: UniProtKB regulation of blood pressure Inferred from mutant phenotype. Source: UniProtKB response to interferon-gamma Ref.12 Ref.14 Ref.17 Ref.21 Inferred from direct assay. Source: UniProtKB response to lipopolysaccharide Ref.12 Ref.14 Ref.21 Inferred from direct assay. Source: UniProtKB response to pain Inferred from sequence or structural similarity. Source: UniProtKB response to tumor necrosis factor Ref.14 Inferred from direct assay. Source: UniProtKB tetrahydrobiopterin biosynthetic process Ref.12 Ref.14 Ref.44 Inferred from direct assay. Source: UniProtKB tetrahydrofolate biosynthetic process Inferred from electronic annotation. Source: InterPro
Cellular component	cytoplasmic vesicle Inferred from direct assay. Source: UniProtKB cytosol Ref.11 Inferred from direct assay. Source: UniProtKB nucleus Ref.24 Inferred from direct assay. Source: UniProtKB protein complex Inferred from direct assay. Source: UniProtKB
Molecular function	GTP binding Ref.9 Ref.19 Inferred from direct assay. Source: UniProtKB GTP cyclohydrolase I activity Ref.8 Ref.24 Ref.29 Inferred from direct assay. Source: UniProtKB protein homodimerization activity Inferred from physical interaction. Source: UniProtKB zinc ion binding Ref.19 Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
AHSA1	O95433	3	EBI-958183,EBI-448610
CNRIP1	Q96F85	2	EBI-958183,EBI-958255
HSPA8	P11142	2	EBI-958183,EBI-351896
RAB26	Q9ULW5	2	EBI-958183,EBI-958239
RLF	Q13129	2	EBI-958183,EBI-958266
SP3	Q02447	2	EBI-958183,EBI-348158

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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 250

250

GTP cyclohydrolase 1

PRO_0000119478

Sites

Metal binding

141

1

Zinc

Metal binding

144

1

Zinc

Metal binding

212

1

Zinc

Amino acid modifications

Modified residue

81

1

Phosphoserine Ref.27

Natural variations

Alternative sequence

210 – 250

41

Missing in isoform GCH-3.

VSP_001610

Alternative sequence

210 – 233

24

HMCMV…TMLGV → KSNKYNKGLSPLLSSCHLFV AILK in isoform GCH-4.

VSP_001611

Alternative sequence

210 – 213

4

HMCM → SAEP in isoform GCH-2.

VSP_001612

Alternative sequence

214 – 250

37

Missing in isoform GCH-2.

VSP_001613

Alternative sequence

234 – 250

17

Missing in isoform GCH-4.

VSP_001614

Natural variant

15

1

G → D in HGCH-3.

VAR_002632

Natural variant

23

1

P → L in DYT5. Ref.34

VAR_002633

Natural variant

71

1

L → Q in DYT5. Ref.36

VAR_016888

Natural variant

74

1

A → V in DYT5. Ref.36

VAR_016889

Natural variant

79

1

L → P in DYT5. Ref.30

VAR_002634

Natural variant

83

1

G → A in DYT5. Ref.36 Ref.41

VAR_016890

Natural variant

88 – 89

2

Missing in DYT5.

VAR_016891

Natural variant

88

1

R → P in DYT5. Ref.32

VAR_002635

Natural variant

88

1

R → W in DYT5. Ref.29

VAR_002636

Natural variant

90

1

G → V in DYT5. Ref.40

VAR_016892

Natural variant

102

1

M → K in DYT5. Ref.38

VAR_002637

Natural variant

102

1

M → R in DYT5. Ref.38

VAR_016893

Natural variant

106

1

T → I in DYT5. Ref.44

VAR_054112

Natural variant

108

1

G → D in GCH1D; phenotype presenting with dystonia and motor delay. Ref.35

VAR_016894

Natural variant

115

1

D → N in DYT5. Ref.34

VAR_016895

Natural variant

134

1

D → V in DYT5. Ref.29

VAR_002638

Natural variant

135

1

I → K in DYT5. Ref.39

VAR_016896

Natural variant

141

1

C → R in DYT5. Ref.38

VAR_016897

Natural variant

141

1

C → W in DYT5. Ref.38

VAR_002639

Natural variant

144

1

H → P in DYT5. Ref.31

VAR_002640

Natural variant

153

1

H → P in DYT5. Ref.32

VAR_002641

Natural variant

163

1

L → R in DYT5. Ref.42

VAR_016898

Natural variant

176

1

S → T in DYT5. Ref.38

VAR_016899

Natural variant

178

1

R → S in DYT5. Ref.33 Ref.38 Ref.41

VAR_002642

Natural variant

180

1

Q → R in DYT5. Ref.41

VAR_016900

Natural variant

184

1

R → H in GCH1D; severe hyperphenylalaninemia. Ref.30

VAR_002643

Natural variant

186

1

T → K in DYT5. Ref.38

VAR_002644

Natural variant

191

1

V → I in DYT5. Ref.36

VAR_016901

Natural variant

199

1

P → L in DYT5. Ref.41

VAR_016902

Natural variant

201

1

G → E in DYT5. Ref.29 Ref.41

VAR_002645

Natural variant

203

1

G → R in DYT5. Ref.32

VAR_002646

Natural variant

211

1

M → I in GCH1D; severe hyperphenylalaninemia. Ref.30

VAR_002647

Natural variant

211

1

M → V in DYT5. Ref.36

VAR_016903

Natural variant

213

1

M → V in DYT5. Ref.42

VAR_016904

Natural variant

221

1

M → T in GCH1D; a patient presenting with dystonia and motor delay; compound heterozygote for an additional deletion. Ref.35

VAR_016905

Natural variant

224

1

K → R in GCH1D and DYT5; phenotype presenting with dystonia and myoclonus. Ref.35 Ref.32 Ref.43

VAR_002648

Natural variant

234

1

F → S in DYT5. Ref.32

VAR_002649

Natural variant

241

1

R → W in DYT5. Ref.36

VAR_016906

Natural variant

249

1

R → S in DYT5. Ref.37

VAR_016907

Experimental info

Sequence conflict

11

1

E → G in AAD38866. Ref.4

Sequence conflict

206

1

V → I in CAA78908. Ref.7

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

250

Helix Strand Turn

Details...

Helix

61 – 81

21

Helix

91 – 93

3

Helix

94 – 102

9

Turn

103 – 106

4

Helix

108 – 110

3

Turn

113 – 115

3

Beta strand

130 – 141

12

Turn

142 – 144

3

Beta strand

147 – 156

10

Helix

165 – 176

12

Beta strand

177 – 180

4

Helix

182 – 197

16

Beta strand

202 – 210

9

Helix

211 – 214

4

Turn

215 – 217

3

Beta strand

224 – 230

7

Helix

233 – 236

4

Helix

238 – 248

11

Sequences

	Sequence		Length	Mass (Da)
	Isoform GCH-1 [UniParc]. Last modified July 1, 1993. Version 1. Checksum: B8A0CB344C598B9A	FASTA	250	27,903
	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
	Isoform GCH-2. Checksum: 021D95DE6B33E02A	FASTA	213	23,516
	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 VQERLTKQIA VAITEALRPA GVGVVVEATS AEP
	Isoform GCH-3. Checksum: 8B33E02A53DF1259	FASTA	209	23,131
	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 VQERLTKQIA VAITEALRPA GVGVVVEAT
	Isoform GCH-4. Checksum: 7100FBD83BFDB2C9	FASTA	233	25,775
	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 VQERLTKQIA VAITEALRPA GVGVVVEATK SNKYNKGLSP LLSSCHLFVA ILK

References

	« Hide 'large scale' referencesShow '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: 1520321] [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: 8068008] [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: 8695054] [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: 11284739] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS GCH-1 AND GCH-4). Tissue: Myelomonocyte.
[5]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM GCH-1). Tissue: Brain.
[6]	"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: 8666288] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-114. Tissue: Granulocyte.
[7]	"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: 1482676] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 60-242.
[8]	"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: 7730309] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 116-209.
[9]	"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: 3753653] [Abstract] Cited for: ENZYME ACTIVITY, ENZYME REGULATION.
[10]	"Human liver GTP cyclohydrolase I: purification and some properties." Shen R.-S., Alam A., Zhang Y.X. Biochimie 71:343-349(1989) [PubMed: 2500984] [Abstract] Cited for: BIOPHYSICOCHEMICAL PROPERTIES.
[11]	"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: 2463916] [Abstract] Cited for: ENZYME ACTIVITY, SUBCELLULAR LOCATION.
[12]	"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: 7678411] [Abstract] Cited for: INDUCTION.
[13]	"Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes." Thoeny B., Blau N. Hum. Mutat. 10:11-20(1997) [PubMed: 9222755] [Abstract] Cited for: REVIEW ON VARIANTS.
[14]	"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: 9445252] [Abstract] Cited for: FUNCTION, INDUCTION.
[15]	"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: 12176133] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[16]	"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: 12002810] [Abstract] Cited for: INDUCTION.
[17]	"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: 12607127] [Abstract] Cited for: INDUCTION.
[18]	"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: 14646243] [Abstract] Cited for: INDUCTION.
[19]	"GTP cyclohydrolase I utilizes metal-free GTP as its substrate." Suzuki T., Kurita H., Ichinose H. Eur. J. Biochem. 271:349-355(2004) [PubMed: 14717702] [Abstract] Cited for: ENZYME REGULATION.
[20]	"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: 16338639] [Abstract] Cited for: FUNCTION.
[21]	"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: 15604419] [Abstract] Cited for: INDUCTION.
[22]	"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: 15649650] [Abstract] Cited for: INDUCTION.
[23]	"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: 16848765] [Abstract] Cited for: SUBUNIT.
[24]	"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: 16778797] [Abstract] Cited for: ENZYME ACTIVITY, ENZYME REGULATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[25]	"A yeast 2-hybrid analysis of human GTP cyclohydrolase I protein interactions." Swick L., Kapatos G. J. Neurochem. 97:1447-1455(2006) [PubMed: 16696853] [Abstract] Cited for: INTERACTION WITH AHSA1 AND GCHFR.
[26]	"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. , 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: 17057711] [Abstract] Cited for: FUNCTION.
[27]	"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: 17704208] [Abstract] Cited for: PHOSPHORYLATION AT SER-81.
[28]	"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: 11087827] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 55-250, SUBUNIT, ZINC-BINDING SITES.
[29]	"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: 7874165] [Abstract] Cited for: VARIANTS DYT5 TRP-88; VAL-134 AND GLU-201.
[30]	"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: 7501255] [Abstract] Cited for: VARIANT DYT5 PRO-79, VARIANTS GCH1D HIS-184 AND ILE-211.
[31]	"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: 8957022] [Abstract] Cited for: VARIANT DYT5 PRO-144.
[32]	"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: 8852666] [Abstract] Cited for: VARIANTS DYT5 PRO-88; PRO-153; ARG-203; ARG-224 AND SER-234.
[33]	"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: 9120469] [Abstract] Cited for: VARIANT DYT5 SER-178.
[34]	"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: 9328244] [Abstract] Cited for: VARIANTS DYT5 LEU-23 AND ASN-115.
[35]	"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: 9667588] [Abstract] Cited for: VARIANTS GCH1D ASP-108; THR-221 AND ARG-224.
[36]	"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: 9778264] [Abstract] Cited for: VARIANTS DYT5 GLN-71; VAL-74; ALA-83; ILE-191; VAL-211 AND TRP-241.
[37]	"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: 10987649] [Abstract] Cited for: VARIANT DYT5 SER-249.
[38]	"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: 10582612] [Abstract] Cited for: VARIANTS DYT5 ARG-102; LYS-102; ARG-141; TRP-141; THR-176; SER-178 AND LYS-186.
[39]	"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: 10208576] [Abstract] Cited for: VARIANT DYT5 LYS-135.
[40]	"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: 10076897] [Abstract] Cited for: VARIANT DYT5 VAL-90.
[41]	"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: 10825351] [Abstract] Cited for: VARIANTS DYT5 ALA-83; 88-ARG-GLN-89 DEL; SER-178; ARG-180; LEU-199 AND GLU-201.
[42]	"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: 11113234] [Abstract] Cited for: VARIANTS DYT5 ARG-163 AND VAL-213.
[43]	"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: 12391354] [Abstract] Cited for: VARIANT DYT5 ARG-224.
[44]	"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: 17101830] [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

EMBLGenBankDDBJ

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.
BC025415 mRNA. Translation: AAH25415.1.
L29478 Genomic DNA. Translation: AAB42186.1.
Z30952 Genomic DNA. Translation: CAA83213.1.
Z16418 mRNA. Translation: CAA78908.1.
U19259 , U19256, U19257, U19258 Genomic DNA. Translation: AAB60633.1.

IPI

IPI00027492.
IPI00220702.
IPI00220703.
IPI00335632.

PIR

PC1117. G01630.
JC1225.

RefSeq

NP_000152.1.
NP_001019195.1.
NP_001019241.1.
NP_001019242.1.

UniGene

Hs.86724

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1FB1	X-ray	3.10	A/B/C/D/E	55-250	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P30793. 8 interactions.

STRING

P30793.

PTM databases

PhosphoSite

P30793.

Proteomic databases

PRIDE

P30793.

Genome annotation databases

Ensembl

ENST00000254299; ENSP00000254299; ENSG00000131979; Homo sapiens. [Genome view]
ENST00000395514; ENSP00000378890; ENSG00000131979; Homo sapiens. [Genome view]
ENST00000395521; ENSP00000378892; ENSG00000131979; Homo sapiens. [Genome view]
ENST00000395524; ENSP00000378895; ENSG00000131979; Homo sapiens. [Genome view]

GeneID

2643.

KEGG

hsa:2643.

UCSC

uc001xbh.1. human.
uc001xbj.1. human.
uc001xbk.1. human.
uc001xbl.1. human.

Organism-specific databases

CTD

2643.

GeneCards

GC14M054378.

H-InvDB

HIX0011677.

HGNC

HGNC:4193. GCH1.

MIM

128230. phenotype.
233910. phenotype.
600225. gene.

Orphanet

255. Dystonia, dopa-responsive.
98808. Dystonia, dopa-responsive, autosomal dominant.
2102. GTP cyclohydrolase I deficiency.

PharmGKB

PA28608.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P30793.

HOVERGEN

P30793.

OMA

ARIVEMF.

Enzyme and pathway databases

BioCyc

MetaCyc:MON-13411.

BRENDA

3.5.4.16. 247.

Gene expression databases

ArrayExpress

P30793.

Bgee

P30793.

CleanEx

HS_GCH1.

Genevestigator

P30793.

GermOnline

ENSG00000131979. Homo sapiens.

Family and domain databases

InterPro

IPR001474. GTP_CycHdrlase_I.
IPR020602. GTP_CycHdrlase_I/CN_OxRdtase.
IPR018234. GTP_CycHdrlase_I_CS.
[Graphical view]

PANTHER

PTHR11109. GTP_cyclohydro_I. 1 hit.

Pfam

PF01227. GTP_cyclohydroI. 1 hit.
[Graphical view]

ProDom

PD003330. GTP_cyclohydroI. 1 hit.
[Graphical view] [Entries sharing at least one domain]

TIGRFAMs

TIGR00063. folE. 1 hit.

PROSITE

PS00859. GTP_CYCLOHYDROL_1_1. 1 hit.
PS00860. GTP_CYCLOHYDROL_1_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

10420.

SOURCE

Search...

Entry information

Entry name

GCH1_HUMAN

Accession

Primary (citable) accession number: P30793
Secondary accession number(s): Q9Y4I8

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1993
Last sequence update:	July 1, 1993
Last modified:	November 3, 2009
This is version 110 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.