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Event: 935

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

KE2 : Decrease, GTPCH-1

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Decrease, GTPCH-1
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
endothelial cell of vascular tree

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
proteasome complex disassembly GTP cyclohydrolase 1 decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Hypertension KeyEvent Brendan Ferreri-Hanberry (send email) Not under active development Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Bos taurus Bos taurus High NCBI
Mus musculus Mus musculus High NCBI
Rattus norvegicus Rattus norvegicus Low NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages Not Specified

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific Not Specified

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

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

List of the literature that was cited for this KE description. More help

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.