ID:GCH1_HUMAN DESCRIPTION: RecName: Full=GTP cyclohydrolase 1; EC=3.5.4.16; AltName: Full=GTP cyclohydrolase I; Short=GTP-CH-I; 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. CATALYTIC ACTIVITY: GTP + H(2)O = formate + 2-amino-4-hydroxy-6- (erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate. ENZYME REGULATION: GTP shows a positive allosteric effect, and tetrahydrobiopterin inhibits the enzyme activity. Zinc is required for catalytic activity. Inhibited by Mg(2+). BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=116 uM 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; PATHWAY: Cofactor biosynthesis; 7,8-dihydroneopterin triphosphate biosynthesis; 7,8-dihydroneopterin triphosphate from GTP: step 1/1. SUBUNIT: 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. INTERACTION: O95433:AHSA1; NbExp=3; IntAct=EBI-958183, EBI-448610; P63104:YWHAZ; NbExp=4; IntAct=EBI-958183, EBI-347088; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. TISSUE SPECIFICITY: In epidermis, expressed predominantly in basal undifferentiated keratinocytes and in some but not all melanocytes (at protein level). 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). PTM: Phosphorylated by casein kinase II at Ser-81 in HAECs during oscillatory shear stress; phosphorylation at Ser-81 results in increased enzyme activity. 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. DISEASE: 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. SIMILARITY: Belongs to the GTP cyclohydrolase I family. WEB RESOURCE: Name=BIOMDB; Note=Db of mutations causing tetrahydrobiopterin deficiencies; URL="http://www.bh4.org/biodef1.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GCH1";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P30793
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0006729 tetrahydrobiopterin biosynthetic process GO:0006809 nitric oxide biosynthetic process GO:0008152 metabolic process GO:0008217 regulation of blood pressure GO:0010460 positive regulation of heart rate GO:0014916 regulation of lung blood pressure GO:0032496 response to lipopolysaccharide GO:0034341 response to interferon-gamma GO:0034612 response to tumor necrosis factor GO:0035998 7,8-dihydroneopterin 3'-triphosphate biosynthetic process GO:0042311 vasodilation GO:0042416 dopamine biosynthetic process GO:0042559 pteridine-containing compound biosynthetic process GO:0045776 negative regulation of blood pressure GO:0046654 tetrahydrofolate biosynthetic process GO:0048265 response to pain GO:0050884 neuromuscular process controlling posture GO:0051000 positive regulation of nitric-oxide synthase activity GO:0051066 dihydrobiopterin metabolic process GO:0051186 cofactor metabolic process GO:0051260 protein homooligomerization GO:0051291 protein heterooligomerization GO:0065003 macromolecular complex assembly GO:2000121 regulation of removal of superoxide radicals
U66095 - Homo sapiens cell-line THP-1 GTP cyclohydrolase I mRNA, complete cds. U66097 - Homo sapiens cell-line THP-1 GTP cyclohydrolase I mRNA, complete cds. BC025415 - Homo sapiens GTP cyclohydrolase 1, mRNA (cDNA clone MGC:12737 IMAGE:4129035), complete cds. U19523 - Human GTP cyclohydrolase I mRNA, complete cds. Z29433 - Homo sapiens mRNA for GTP cyclohydrase I, clone 1. S44053 - GTP cyclohydrolase I {alternatively spliced, clone hGCH-2} [human, liver, mRNA, 994 nt]. AF321276 - Homo sapiens GTP cyclohydrolase I mRNA, partial cds. AY137463 - Homo sapiens GTP cyclohydrolase I type IV mRNA, partial cds; alternatively spliced. AY137464 - Homo sapiens GTP cyclohydrolase I type V mRNA, partial cds; alternatively spliced. AY137465 - Homo sapiens GTP cyclohydrolase I type VI mRNA, partial cds; alternatively spliced. S44049 - GTP cyclohydrolase I {clone hGCH-1} [human, liver, mRNA, 1180 nt]. Z29434 - Homo sapiens mRNA for GTP cyclohydrase I, clone 2. CR536551 - Homo sapiens full open reading frame cDNA clone RZPDo834G0222D for gene GCH1, GTP cyclohydrolase 1 (dopa-responsive dystonia); complete cds, incl. stopcodon. DQ892998 - Synthetic construct clone IMAGE:100005628; FLH191518.01X; RZPDo839E0277D GTP cyclohydrolase 1 (dopa-responsive dystonia) (GCH1) gene, encodes complete protein. DQ896245 - Synthetic construct Homo sapiens clone IMAGE:100010705; FLH191514.01L; RZPDo839E0267D GTP cyclohydrolase 1 (dopa-responsive dystonia) (GCH1) gene, encodes complete protein. Z16418 - Homo sapiens mRNA for GTP cyclohydrolase I. S43856 - GTP cyclohydrolase I {clone hGCH-3} [human, liver, mRNA, 819 nt]. JD563028 - Sequence 544052 from Patent EP1572962. JD110657 - Sequence 91681 from Patent EP1572962. JD047001 - Sequence 28025 from Patent EP1572962. JD262826 - Sequence 243850 from Patent EP1572962. JD088759 - Sequence 69783 from Patent EP1572962. JD499469 - Sequence 480493 from Patent EP1572962. JD119947 - Sequence 100971 from Patent EP1572962. JD173666 - Sequence 154690 from Patent EP1572962. JD374094 - Sequence 355118 from Patent EP1572962. JD250704 - Sequence 231728 from Patent EP1572962. JD090788 - Sequence 71812 from Patent EP1572962. JD314809 - Sequence 295833 from Patent EP1572962. JD081446 - Sequence 62470 from Patent EP1572962. JD047003 - Sequence 28027 from Patent EP1572962. JD331457 - Sequence 312481 from Patent EP1572962. JD489780 - Sequence 470804 from Patent EP1572962. JD221038 - Sequence 202062 from Patent EP1572962. JD070679 - Sequence 51703 from Patent EP1572962. JD508160 - Sequence 489184 from Patent EP1572962.
Biochemical and Signaling Pathways
BioCyc Knowledge Library PWY-5663 - tetrahydrobiopterin de novo biosynthesis
Reactome (by CSHL, EBI, and GO)
Protein P30793 (Reactome details) participates in the following event(s):
R-HSA-1474158 GCHFR binds to GCH1 and negatively regulates its activity R-HSA-1474146 GCH1 reduces GTP to dihydroneopterin triphosphate R-HSA-1474151 Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation R-HSA-8978934 Metabolism of cofactors R-HSA-196854 Metabolism of vitamins and cofactors R-HSA-1430728 Metabolism
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
