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Gene Review

Gch1  -  GTP cyclohydrolase 1

Rattus norvegicus

Synonyms: GTP cyclohydrolase I, GTP-CH-I, Gch
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Disease relevance of Gch


Psychiatry related information on Gch


High impact information on Gch


Chemical compound and disease context of Gch


Biological context of Gch


Anatomical context of Gch


Associations of Gch with chemical compounds

  • Both cell types were also transduced with GCH1 to provide the obligate TH cofactor, tetrahydrobiopterin [21].
  • These changes were accompanied by increased TH, GCH and NE transporter mRNAs [22].
  • GTP cyclohydrolase I (GCH1) is the first and rate-limiting enzyme in the synthesis of BH(4), an essential cofactor for tyrosine hydroxylase and nitric oxide synthase in dopamine and nitric oxide production, respectively [17].
  • We have demonstrated that 1 week following kainic acid there was an increase in striatal GCH1 mRNA, protein, and activity [17].
  • Inhibition of GTP cyclohydrolase I (GTPCH) has been used as a selective tool to assess the role of de novo synthesis of (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4) in a biological system [23].

Regulatory relationships of Gch


Other interactions of Gch

  • The increased BH(4) synthesis by V-1 overexpression was dose dependently inhibited by pretreatment with diaminohydroxypyrimidine (DAHP), an inhibitor of GTP-cyclohydrolase I, which is the rate-limiting enzyme for the biosynthesis of BH(4), concomitantly with the loss of protective effect afforded by V-1 overexpression [29].
  • Furthermore, the abnormal expression of DeltaFosB, prodynorphin and preproenkephalin mRNA within the striatal projection neurons normally seen in dyskinetic animals was completely reversed by TH-GCH1 gene transfer [30].
  • Crystal structure of the stimulatory complex of GTP cyclohydrolase I and its feedback regulatory protein GFRP [8].
  • Dexamethasone prevented the coordinate induction of GTP cyclohydrolase I with NOS2 after exposure to interleukin-1beta and interferon-gamma and also the increase in intracellular BH4 content in cytokine-treated CMEC [31].
  • Regulation of GTP cyclohydrolase I gene expression and tetrahydrobiopterin content in cultured sympathetic neurons by leukemia inhibitory factor and ciliary neurotrophic factor [32].

Analytical, diagnostic and therapeutic context of Gch


  1. Coexpression of tyrosine hydroxylase, GTP cyclohydrolase I, aromatic amino acid decarboxylase, and vesicular monoamine transporter 2 from a helper virus-free herpes simplex virus type 1 vector supports high-level, long-term biochemical and behavioral correction of a rat model of Parkinson's disease. Sun, M., Kong, L., Wang, X., Holmes, C., Gao, Q., Zhang, G.R., Pfeilschifter, J., Goldstein, D.S., Geller, A.I. Hum. Gene Ther. (2004) [Pubmed]
  2. Behavioral correction of Parkinsonian rats following the transplantation of immortalized fibroblasts genetically modified with TH and GCH genes. Chen, S., Xianwen, C., Dehua, X., Zhenguo, L., Lingfei, X., Smith, S.W., Zhongcheng, Z. Parkinsonism Relat. Disord. (2003) [Pubmed]
  3. Expression of nitric oxide synthases and GTP cyclohydrolase I in the ventilatory and limb muscles during endotoxemia. Hussain, S.N., Giaid, A., El Dawiri, Q., Sakkal, D., Hattori, R., Guo, Y. Am. J. Respir. Cell Mol. Biol. (1997) [Pubmed]
  4. Increased blood flow causes coordinated upregulation of arterial eNOS and biosynthesis of tetrahydrobiopterin. Lam, C.F., Peterson, T.E., Richardson, D.M., Croatt, A.J., d'Uscio, L.V., Nath, K.A., Katusic, Z.S. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  5. Inhibition of tetrahydrobiopterin synthesis reduces in vivo nitric oxide production in experimental endotoxic shock. Bune, A.J., Brand, M.P., Heales, S.J., Shergill, J.K., Cammack, R., Cook, H.T. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  6. The effects of electroconvulsive shock on catecholamine function in the locus ceruleus and hippocampus. Weiner, N., Hossain, M.A., Masserano, J.M. J. Neural Transm. Suppl. (1991) [Pubmed]
  7. Biopterin cofactor biosynthesis: independent regulation of GTP cyclohydrolase in adrenal medulla and cortex. Viveros, O.H., Lee, C.L., Abou-Donia, M.M., Nixon, J.C., Nichol, C.A. Science (1981) [Pubmed]
  8. Crystal structure of the stimulatory complex of GTP cyclohydrolase I and its feedback regulatory protein GFRP. Maita, N., Okada, K., Hatakeyama, K., Hakoshima, T. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  9. Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer. Kirik, D., Georgievska, B., Burger, C., Winkler, C., Muzyczka, N., Mandel, R.J., Bjorklund, A. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  10. Bacterial translocation up-regulates GTP-cyclohydrolase I in mesenteric vasculature of cirrhotic rats. Wiest, R., Cadelina, G., Milstien, S., McCuskey, R.S., Garcia-Tsao, G., Groszmann, R.J. Hepatology (2003) [Pubmed]
  11. Double transduction with GTP cyclohydrolase I and tyrosine hydroxylase is necessary for spontaneous synthesis of L-DOPA by primary fibroblasts. Bencsics, C., Wachtel, S.R., Milstien, S., Hatakeyama, K., Becker, J.B., Kang, U.J. J. Neurosci. (1996) [Pubmed]
  12. Long-term doxycycline-controlled expression of human tyrosine hydroxylase after direct adenovirus-mediated gene transfer to a rat model of Parkinson's disease. Corti, O., Sánchez-Capelo, A., Colin, P., Hanoun, N., Hamon, M., Mallet, J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  13. Glucocorticoid regulation of nitric oxide and tetrahydrobiopterin in a rat model of endotoxic shock. Hattori, Y., Akimoto, K., Nakanishi, N., Kasai, K. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  14. GTP cyclohydrolase I feedback regulatory protein-dependent and -independent inhibitors of GTP cyclohydrolase I. Yoneyama, T., Wilson, L.M., Hatakeyama, K. Arch. Biochem. Biophys. (2001) [Pubmed]
  15. Response of tyrosine hydroxylase and GTP cyclohydrolase I gene expression to estrogen in brain catecholaminergic regions varies with mode of administration. Serova, L.I., Maharjan, S., Huang, A., Sun, D., Kaley, G., Sabban, E.L. Brain Res. (2004) [Pubmed]
  16. Cloning and sequencing of cDNA encoding rat GTP cyclohydrolase I. The first enzyme of the tetrahydrobiopterin biosynthetic pathway. Hatakeyama, K., Inoue, Y., Harada, T., Kagamiyama, H. J. Biol. Chem. (1991) [Pubmed]
  17. GTP cyclohydrolase I induction in striatal astrocytes following intrastriatal kainic acid lesion. Foster, J.A., Christopherson, P.L., Levine, R.A. J. Chem. Neuroanat. (2002) [Pubmed]
  18. Brain transplantation of human neural stem cells transduced with tyrosine hydroxylase and GTP cyclohydrolase 1 provides functional improvement in animal models of Parkinson disease. Kim, S.U., Park, I.H., Kim, T.H., Kim, K.S., Choi, H.B., Hong, S.H., Bang, J.H., Lee, M.A., Joo, I.S., Lee, C.S., Kim, Y.S. Neuropathology : official journal of the Japanese Society of Neuropathology. (2006) [Pubmed]
  19. Coinduction of GTP cyclohydrolase I and inducible NO synthase in rat osteoblasts during space flight: apoptotic and self-protective response? Kumei, Y., Morita, S., Nakamura, H., Akiyama, H., Hirano, M., Shimokawa, H., Ohya, K. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  20. Nitric oxide (NO) pretreatment increases cytokine-induced NO production in cultured rat hepatocytes by suppressing GTP cyclohydrolase I feedback inhibitory protein level and promoting inducible NO synthase dimerization. Park, J.H., Na, H.J., Kwon, Y.G., Ha, K.S., Lee, S.J., Kim, C.K., Lee, K.S., Yoneyama, T., Hatakeyama, K., Kim, P.K., Billiar, T.R., Kim, Y.M. J. Biol. Chem. (2002) [Pubmed]
  21. A site-specific mutation of tyrosine hydroxylase reduces feedback inhibition by dopamine in genetically modified cells grafted in parkinsonian rats. Chang, J.W., Lee, W.Y., Milstien, S., Kang, U.J. J. Neurochem. (2002) [Pubmed]
  22. Regulation of noradrenergic function by inflammatory cytokines and depolarization. Li, W., Knowlton, D., Woodward, W.R., Habecker, B.A. J. Neurochem. (2003) [Pubmed]
  23. The mechanism of potent GTP cyclohydrolase I inhibition by 2,4-diamino-6-hydroxypyrimidine: requirement of the GTP cyclohydrolase I feedback regulatory protein. Kolinsky, M.A., Gross, S.S. J. Biol. Chem. (2004) [Pubmed]
  24. Endothelin-1 inhibits induction of nitric oxide synthase and GTP cyclohydrolase I in rat mesangial cells. Hirahashi, J., Nakaki, T., Hishikawa, K., Marumo, T., Yasumori, T., Hayashi, M., Suzuki, H., Saruta, T. Pharmacology (1996) [Pubmed]
  25. Glial cell line-derived neurotrophic factor up-regulates GTP-cyclohydrolase I activity and tetrahydrobiopterin levels in primary dopaminergic neurones. Bauer, M., Suppmann, S., Meyer, M., Hesslinger, C., Gasser, T., Widmer, H.R., Ueffing, M. J. Neurochem. (2002) [Pubmed]
  26. Interleukin 1 beta and cAMP trigger the expression of GTP cyclohydrolase I in rat renal mesangial cells. Plüss, C., Werner, E.R., Blau, N., Wachter, H., Pfeilschifter, J. Biochem. J. (1996) [Pubmed]
  27. Tetrahydrobiopterin as a mediator of PC12 cell proliferation induced by EGF and NGF. Anastasiadis, P.Z., Bezin, L., Imerman, B.A., Kuhn, D.M., Louie, M.C., Levine, R.A. Eur. J. Neurosci. (1997) [Pubmed]
  28. Induction of tetrahydrobiopterin synthesis in rat cardiac myocytes: impact on cytokine-induced NO generation. Kasai, K., Hattori, Y., Banba, N., Hattori, S., Motohashi, S., Shimoda, S., Nakanishi, N., Gross, S.S. Am. J. Physiol. (1997) [Pubmed]
  29. Overexpression of V-1 prevents nitric oxide-induced cell death: involvement of enhanced tetrahydrobiopterin biosynthesis. Yuyama, K., Yamamoto, H., Nakamura, K., Nishizaki, I., Yamakuni, T., Song, S.Y., Sora, I., Nagatsu, T., Yamamoto, T. J. Neurosci. Res. (2003) [Pubmed]
  30. Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors. Carlsson, T., Winkler, C., Burger, C., Muzyczka, N., Mandel, R.J., Cenci, A., Björklund, A., Kirik, D. Brain (2005) [Pubmed]
  31. Glucocorticoids regulate inducible nitric oxide synthase by inhibiting tetrahydrobiopterin synthesis and L-arginine transport. Simmons, W.W., Ungureanu-Longrois, D., Smith, G.K., Smith, T.W., Kelly, R.A. J. Biol. Chem. (1996) [Pubmed]
  32. Regulation of GTP cyclohydrolase I gene expression and tetrahydrobiopterin content in cultured sympathetic neurons by leukemia inhibitory factor and ciliary neurotrophic factor. Stegenga, S.L., Hirayama, K., Kapatos, G. J. Neurochem. (1996) [Pubmed]
  33. Nitric oxide formation in acutely rejecting cardiac allografts correlates with GTP cyclohydrolase I activity. Pieper, G.M., Nilakantan, V., Halligan, N.L., Khanna, A.K., Hilton, G., Vásquez-Vivar, J. Biochem. J. (2005) [Pubmed]
  34. Purification and cloning of the GTP cyclohydrolase I feedback regulatory protein, GFRP. Milstien, S., Jaffe, H., Kowlessur, D., Bonner, T.I. J. Biol. Chem. (1996) [Pubmed]
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