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Beschreibung

GTP cyclohydrolase 1 (UniProt: P30793, also known as EC: 3.5.4.16, GTP cyclohydrolase, GTP-CH-I) is encoded by the GCH1 (also known as DYT5, GCH) gene (Gene ID: 2643) in human. GTP-CH-1 is a functional enzyme that is involved in step 1 of the subpathway for synthesis of 7, 8-dihydroneopterin triphosphate from GTP. It is shown to positively regulate nitric oxide synthesis in umbilical vein endothelial cells. It is expressed in epidermis and its expression is high in basal undifferentiated keratinocytes. Four isoforms of GTP-CH-1 are reported that are produced by alternative splicing. Its activity is inhibited by tetrahydrobiopterin and GTP has a positive allosteric effect on its activity. It contains three zinc binding sites (aa 141, 144, 211) and Zn2+ is shown to be essential for its catalytic activity. Its activity is also up-regulated by IFN-gamma, TNF, interleukin-1 beta, bacterial lipopolysaccharides and phenylalanine, and is down-regulated by dibutyryl-cAMP, iloprost and 8-bromo-cGMP in HUVEC. Up-regulation of its activity stimulates the production of tetrahydrobiopterin that results in elevation of endothelial nitric oxide synthase activity. GTP-CH-1 is phosphorylated by casein kinase II at serine 81 in aortic endothelial cells during oscillatory shear stress that results in increased enzyme activity. Mutations in GCH1 gene can result in hyperphenylalaninemia and depletion of dopamine and serotonin resulting in psychomotor retardation, tonicity disorders, convulsions, and abnormal movements.