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Event: 935
Key Event Title
KE2 : Decrease, GTPCH-1
Short name
Biological Context
Level of Biological Organization |
---|
Cellular |
Cell term
Cell term |
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endothelial cell of vascular tree |
Organ term
Key Event Components
Process | Object | Action |
---|---|---|
proteasome complex disassembly | GTP cyclohydrolase 1 | decreased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
Hypertension | KeyEvent | Frazer Lowe (send email) | Not under active development | Under Development |
Taxonomic Applicability
Life Stages
Life stage | Evidence |
---|---|
All life stages | Not Specified |
Sex Applicability
Term | Evidence |
---|---|
Unspecific | Not Specified |
Key Event Description
Guanosine triphosphate cyclohydrolase-1 (GTPCH-1) is the rate-limiting enzyme in the de novo biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for endothelial nitric oxide synthase (eNOS) and nitric oxide generation (Wang et al., 2008). GTPCH-1 catalyzes the rearrangement of GTP to 7-dihydroneopterin triphosphate, which is converted to BH4 through sequential actions of pyruvoyl tetrahydrobiopterin synthase and sepiapterin reductase. GTPCH-1 activity is regulated in a negative feedback by levels of BH4 which promotes binding of GTPCH-1 with its inhibitor GTPCH feedback regulatory protein (GFRP), but phosphorylation of GTPCH-1 reduces its binding to GFRP and prevents this negative feedback (Chen et al., 2011). Loss or inactivation of GTPCH-1 results in decreased BH4 levels, which causes eNOS uncoupling.
How It Is Measured or Detected
The activity of GTPCH-1 can be detected through the quantification of neopterin by high-performance liquid chromatography (HPLC) after the conversion of enzymatically formed dihydroneopterin triphosphate into neopterin by sequential iodine oxidation and dephosphorylation.
Domain of Applicability
Several studies showed decreased GTPCH-1 activity and/or protein expression in cardiac reperfusion patients, bovine endothelial cells, a mouse model of diabetes and a rat model of hypertension (Cervantes-Pérez et al., 2012; Abdelghany et al., 2017; Jayaram et al., 2015; Zhao et al., 2013).
Furthermore, mice deficient in GTPCH-1 demonstrate decreased BH4 bioavailability, increased eNOS uncoupling, pulmonary vascular resistance and pulmonary hypertension (Belik et al. 2011, Nandi et al. 2005, Khoo et al. 2005).
References
AbdelGhany, T., Ismail, R., Elmahdy, M., Mansoor F, Zweier J, Lowe, F., and Zweier, JL. (2017). Cigarette Smoke Constituents Cause Endothelial Nitric Oxide Synthase Dysfunction and Uncoupling due to Depletion of Tetrahydrobiopterin with Degradation of GTP Cyclohydrolase. Nitric Oxide (Under review).
Belik J, McIntyre BA, Enomoto M, Pan J, Grasemann H, Vasquez-Vivar J. Pulmonary hypertension in the newborn GTP cyclohydrolase I-deficient mouse. Free Radic Biol Med. 2011, 51(12):2227-33.
Cervantes-Pérez, L.G., Ibarra-Lara, M. de la L., Escalante, B., Del Valle-Mondragón, L., Vargas-Robles, H., Pérez-Severiano, F., Pastelín, G., and Sánchez-Mendoza, M.A. (2012). Endothelial nitric oxide synthase impairment is restored by clofibrate treatment in an animal model of hypertension. Eur. J. Pharmacol. 685, 108–115.
Chen, W., Li, L., Brod, T., Saeed, O., Thabet, S., Jansen, T., Dikalov, S., Weyand, C., Goronzy, J., and Harrison, D.G. (2011). Role of increased guanosine triphosphate cyclohydrolase-1 expression and tetrahydrobiopterin levels upon T cell activation. J. Biol. Chem. 286, 13846–13851.
Jayaram, R., Goodfellow, N., Zhang, M.H., Reilly, S., Crabtree, M., De Silva, R., Sayeed, R., and Casadei, B. (2015). Molecular mechanisms of myocardial nitroso-redox imbalance during on-pump cardiac surgery. Lancet Lond. Engl. 385 Suppl 1, S49.
Khoo JP, Zhao L, Alp NJ, Bendall JK, Nicoli T, Rockett K, et al. Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension. Circulation. 2005;111:2126–33
Nandi M, Miller A, Stidwill R, Jacques TS, Lam AA, Haworth S, et al. Pulmonary hypertension in a GTP-cyclohydrolase 1-deficient mouse. Circulation. 2005;111:2086–90
Wang, S., Xu, J., Song, P., Wu, Y., Zhang, J., Chul Choi, H., and Zou, M.-H. (2008). Acute inhibition of guanosine triphosphate cyclohydrolase 1 uncouples endothelial nitric oxide synthase and elevates blood pressure. Hypertension 52, 484–490.
Zhao, Y., Wu, J., Zhu, H., Song, P., and Zou, M.-H. (2013). Peroxynitrite-dependent zinc release and inactivation of guanosine 5’-triphosphate cyclohydrolase 1 instigate its ubiquitination in diabetes. Diabetes 62, 4247–4256.