API

Event: 935

Key Event Title

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Decrease, GTPCH-1

Short name

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Decrease, GTPCH-1

Key Event Component

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Process Object Action
proteasome complex disassembly GTP cyclohydrolase 1 decreased

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Peptide Oxidation Leading to Hypertension KeyEvent

Stressors

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Level of Biological Organization

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Biological Organization
Cellular

Cell term

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Cell term
endothelial cell of vascular tree


Organ term

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Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens Strong NCBI
Bos taurus Bos taurus Strong NCBI
Mus musculus Mus musculus Strong NCBI
Rattus norvegicus Rattus norvegicus Weak NCBI

Life Stages

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Sex Applicability

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How This Key Event Works

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Guanosine triphosphate cyclohydrolase-1 (GTPCH-1), a homodecameric protein consisting of 25-kDa subunit, 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, which causes eNOS uncoupling.


How It Is Measured or Detected

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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.


Evidence Supporting Taxonomic Applicability

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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).


References

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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).

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.

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.