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Peptide Oxidation leads to Decrease, GTPCH-1
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Exposure to known inducers of oxidative stress such as cigarette smoke extract (AbdelGhany et al., under review) or peroxynitrite (Zhao et al., 2013) causes the loss of GTPCH-1 activity, resulting in decreased levels of tetrahydrobiopterin (BH4) and subsequent uncoupling of endothelial nitric oxide synthase (eNOS).
Evidence Supporting this KER
Several studies demonstrated that GTPCH-1 is also affected by oxidative stress, which provides evidence for moderate biological plausibility. In vitro exposure to chemically synthesized peroxynitrite inhibited GTPCH-1 activity in a dose-dependent manner (Zhao et al., 2013). This inhibition as well as increased ubiquitination of GTPCH-1 were observed in cultured bovine aortic endothelial cells (BAECs) and streptozotocin-induced diabetes in mice following peroxynitrite treatment. Ubiquitination of GTPCH-1 leads to its degradation, which is equivalent to a decrease in GTPCH-1. In another study, GTPCH-1 levels were reduced by cigarette smoke extract (CSE) exposure in BAECs (AbdelGhany et al., under review). There is also evidence that CSE promoted GTPCH-1 degradation by increasing proteasomal activity. Furthermore, cardiac reperfusion patients experienced oxidative stress which was associated with reduced GTPCH-1 activity (Jayaram et al., 2015).
Uncertainties and Inconsistencies
No uncertainties or inconsistencies were found for this KER.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Several studies showed decreased GTPCH-1 activity and/or protein expression under oxidative stress 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., (under review); Jayaram et al., 2015; Zhao et al., 2013).
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.
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
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.