UniProt functional annotation for P30793



	UniProt functional annotation for P30793

UniProt code: P30793.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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. {ECO:0000269|PubMed:12176133, ECO:0000269|PubMed:16338639, ECO:0000269|PubMed:17057711, ECO:0000269|PubMed:8068008, ECO:0000269|PubMed:9445252}.

Catalytic activity: Reaction=GTP + H2O = 7,8-dihydroneopterin 3'-triphosphate + formate + H(+); Xref=Rhea:RHEA:17473, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15740, ChEBI:CHEBI:37565, ChEBI:CHEBI:58462; EC=3.5.4.16; Evidence={ECO:0000269|PubMed:16778797, ECO:0000269|PubMed:2463916, ECO:0000269|PubMed:3753653};

Activity regulation: GTP shows a positive allosteric effect, and tetrahydrobiopterin inhibits the enzyme activity. Zinc is required for catalytic activity. Inhibited by Mg(2+). {ECO:0000269|PubMed:14717702, ECO:0000269|PubMed:16778797, ECO:0000269|PubMed:3753653}.

Biophysicochemical properties: Kinetic parameters: KM=116 uM for GTP {ECO:0000269|PubMed:2500984}; pH dependence: Optimum pH is 7.7 in phosphate buffer. {ECO:0000269|PubMed:2500984}; Temperature dependence: Relatively stable at high temperatures. Retains 50% of its activity after incubation at 70 degrees Celsius for 15 minutes. {ECO:0000269|PubMed:2500984};

Pathway: Cofactor biosynthesis; 7,8-dihydroneopterin triphosphate biosynthesis; 7,8-dihydroneopterin triphosphate from GTP: step 1/1. {ECO:0000305|PubMed:16778797, ECO:0000305|PubMed:2463916, ECO:0000305|PubMed:3753653}.

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. {ECO:0000269|PubMed:11087827, ECO:0000269|PubMed:16696853, ECO:0000269|PubMed:16848765}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:12176133, ECO:0000269|PubMed:16778797, ECO:0000269|PubMed:2463916}. Nucleus {ECO:0000269|PubMed:16778797}.

Tissue specificity: In epidermis, expressed predominantly in basal undifferentiated keratinocytes and in some but not all melanocytes (at protein level). {ECO:0000269|PubMed:16778797}.

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). {ECO:0000269|PubMed:12002810, ECO:0000269|PubMed:12607127, ECO:0000269|PubMed:14646243, ECO:0000269|PubMed:15604419, ECO:0000269|PubMed:15649650, ECO:0000269|PubMed:7678411, ECO:0000269|PubMed:9445252}.

Ptm: Phosphorylated by casein kinase II at Ser-81 in HAECs during oscillatory shear stress; phosphorylation at Ser-81 results in increased enzyme activity. {ECO:0000269|PubMed:17704208}.

Disease: Hyperphenylalaninemia, BH4-deficient, B (HPABH4B) [MIM:233910]: A disease characterized by malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency, and 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. In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia. {ECO:0000269|PubMed:7501255, ECO:0000269|PubMed:9667588}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Dystonia, dopa-responsive (DRD) [MIM:128230]: A form of dystonia that responds to L-DOPA treatment without side effects. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DRD 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. {ECO:0000269|PubMed:10076897, ECO:0000269|PubMed:10208576, ECO:0000269|PubMed:10582612, ECO:0000269|PubMed:10825351, ECO:0000269|PubMed:10987649, ECO:0000269|PubMed:11113234, ECO:0000269|PubMed:12391354, ECO:0000269|PubMed:17101830, ECO:0000269|PubMed:7501255, ECO:0000269|PubMed:7874165, ECO:0000269|PubMed:8852666, ECO:0000269|PubMed:8957022, ECO:0000269|PubMed:9120469, ECO:0000269|PubMed:9328244, ECO:0000269|PubMed:9778264}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the GTP cyclohydrolase I family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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. {ECO:0000269\|PubMed:12176133, ECO:0000269\|PubMed:16338639, ECO:0000269\|PubMed:17057711, ECO:0000269\|PubMed:8068008, ECO:0000269\|PubMed:9445252}.


Catalytic activity:		Reaction=GTP + H2O = 7,8-dihydroneopterin 3'-triphosphate + formate + H(+); Xref=Rhea:RHEA:17473, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15740, ChEBI:CHEBI:37565, ChEBI:CHEBI:58462; EC=3.5.4.16; Evidence={ECO:0000269\|PubMed:16778797, ECO:0000269\|PubMed:2463916, ECO:0000269\|PubMed:3753653};
Activity regulation:		GTP shows a positive allosteric effect, and tetrahydrobiopterin inhibits the enzyme activity. Zinc is required for catalytic activity. Inhibited by Mg(2+). {ECO:0000269\|PubMed:14717702, ECO:0000269\|PubMed:16778797, ECO:0000269\|PubMed:3753653}.
Biophysicochemical properties:		Kinetic parameters: KM=116 uM for GTP {ECO:0000269\|PubMed:2500984}; pH dependence: Optimum pH is 7.7 in phosphate buffer. {ECO:0000269\|PubMed:2500984}; Temperature dependence: Relatively stable at high temperatures. Retains 50% of its activity after incubation at 70 degrees Celsius for 15 minutes. {ECO:0000269\|PubMed:2500984};
Pathway:		Cofactor biosynthesis; 7,8-dihydroneopterin triphosphate biosynthesis; 7,8-dihydroneopterin triphosphate from GTP: step 1/1. {ECO:0000305\|PubMed:16778797, ECO:0000305\|PubMed:2463916, ECO:0000305\|PubMed:3753653}.
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. {ECO:0000269\|PubMed:11087827, ECO:0000269\|PubMed:16696853, ECO:0000269\|PubMed:16848765}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:12176133, ECO:0000269\|PubMed:16778797, ECO:0000269\|PubMed:2463916}. Nucleus {ECO:0000269\|PubMed:16778797}.
Tissue specificity:		In epidermis, expressed predominantly in basal undifferentiated keratinocytes and in some but not all melanocytes (at protein level). {ECO:0000269\|PubMed:16778797}.
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). {ECO:0000269\|PubMed:12002810, ECO:0000269\|PubMed:12607127, ECO:0000269\|PubMed:14646243, ECO:0000269\|PubMed:15604419, ECO:0000269\|PubMed:15649650, ECO:0000269\|PubMed:7678411, ECO:0000269\|PubMed:9445252}.
Ptm:		Phosphorylated by casein kinase II at Ser-81 in HAECs during oscillatory shear stress; phosphorylation at Ser-81 results in increased enzyme activity. {ECO:0000269\|PubMed:17704208}.
Disease:		Hyperphenylalaninemia, BH4-deficient, B (HPABH4B) [MIM:233910]: A disease characterized by malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency, and 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. In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia. {ECO:0000269\|PubMed:7501255, ECO:0000269\|PubMed:9667588}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Dystonia, dopa-responsive (DRD) [MIM:128230]: A form of dystonia that responds to L-DOPA treatment without side effects. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DRD 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. {ECO:0000269\|PubMed:10076897, ECO:0000269\|PubMed:10208576, ECO:0000269\|PubMed:10582612, ECO:0000269\|PubMed:10825351, ECO:0000269\|PubMed:10987649, ECO:0000269\|PubMed:11113234, ECO:0000269\|PubMed:12391354, ECO:0000269\|PubMed:17101830, ECO:0000269\|PubMed:7501255, ECO:0000269\|PubMed:7874165, ECO:0000269\|PubMed:8852666, ECO:0000269\|PubMed:8957022, ECO:0000269\|PubMed:9120469, ECO:0000269\|PubMed:9328244, ECO:0000269\|PubMed:9778264}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the GTP cyclohydrolase I family. {ECO:0000305}.