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Event: 934

Key Event Title

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

KE3 : Decrease, Tetrahydrobiopterin

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, Tetrahydrobiopterin
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Biological Context

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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
biosynthetic process 5,6,7,8-tetrahydrobiopterin 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 Frazer Lowe (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 Moderate 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

Tetrahydrobiopterin (BH4) is an essential cofactor for a group of enzymes including aromatic acid hydroxylases, nitric oxide synthase (NOS) isoforms, and alkylglycerol monooxygenase (Wang et al., 2014). BH4 is synthesized from guanosine triphosphate through sequential reactions catalyzed by enzymes GTPCH-1, pyruvoyl tetrahydropterin synthase, and sepiapterin reductase (Tatham et al., 2009). During NOS catalysis, BH4 donates electrons to the ferrous-dioxygen complex in the oxygenase domain, leading to oxidation of L-arginine to N-hydroxy-Larginine and eventually conversion to citrulline and nitric oxide production (Chen et al., 2011; Crabtree et al., 2009). BH4 also stabilizes dimers of NOS isoforms, which is required for their enzymatic activity. When BH4 levels are decreased or limited, for example under oxidative stress conditions, BH4 can be oxidized to dihydrobiopterin (BH2) and then converted to biopterin. This reduction in BH4 availability results in NOS uncoupling where NOS is uncoupled from L-arginine oxidation and superoxide (or other reactive species) is produced rather than nitric oxide (Carnicer et al., 2012). Decreased BH4 have been demonstrated in a variety of vascular diseases such as hypertension, diabetes and atherosclerosis where endothelial dysfunction occurs.

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

Levels of BH4, BH2 and biopterin levels can be determined by reverse-phase high-performance liquid chromatography (HPLC) followed by electrochemical detection (for BH4) and fluorescence detection (for BH2 and biopterin) (Howells et al., 1986).

A LC-MS/MS method has been published by Zhao et al. (2009), which was validated for detection in human, monkey, dog, rabbit, rat and mouse plasma, and used to support a successful drug approval submission.

ELISA kits for BH4 are also commercially available.

In each case, care must be taken to protect the sample from oxidation, and BH4 is highly redox sensitive.  Dithioerythritol is commonly used as a preservation agent.

Domain of Applicability

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

Decreased BH4 is observed in humans (Jayaram et al., 2015), cows (Abdelghany et al., 2017; Whitsett et al., 2007, Wang et al., 2008), mice (Adlam et al., 2012; Chuaiphichai et al., 2014; Crabtree et al., 2009; Tatham et al., 2009; Wang et al., 2008) and rats (Cervantes-Pérez et al., 2012).

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).

Adlam, D., Herring, N., Douglas, G., De Bono, J.P., Li, D., Danson, E.J., Tatham, A., Lu, C.-J., Jennings, K.A., Cragg, S.J., et al. (2012). Regulation of β-adrenergic control of heart rate by GTP-cyclohydrolase 1 (GCH1) and tetrahydrobiopterin. Cardiovasc. Res. 93, 694–701.

Carnicer, R., Hale, A.B., Suffredini, S., Liu, X., Reilly, S., Zhang, M.H., Surdo, N.C., Bendall, J.K., Crabtree, M.J., Lim, G.B.S., et al. (2012). Cardiomyocyte GTP cyclohydrolase 1 and tetrahydrobiopterin increase NOS1 activity and accelerate myocardial relaxation. Circ. Res. 111, 718–727.

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.

Crabtree, M.J., Tatham, A.L., Al-Wakeel, Y., Warrick, N., Hale, A.B., Cai, S., Channon, K.M., and Alp, N.J. (2009). Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: insights from cells with tet-regulated GTP cyclohydrolase I expression. J. Biol. Chem. 284, 1136–1144.

Chuaiphichai, S., McNeill, E., Douglas, G., Crabtree, M.J., Bendall, J.K., Hale, A.B., Alp, N.J., and Channon, K.M. (2014). Cell-autonomous role of endothelial GTP cyclohydrolase 1 and tetrahydrobiopterin in blood pressure regulation. Hypertension 64, 530–540.

Howells, D.W., Smith, I., and Hyland, K. (1986). Estimation of tetrahydrobiopterin and other pterins in cerebrospinal fluid using reversed-phase high-performance liquid chromatography with electrochemical and fluorescence detection. J. Chromatogr. 381, 285–294.

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.

Tatham, A.L., Crabtree, M.J., Warrick, N., Cai, S., Alp, N.J., and Channon, K.M. (2009). GTP cyclohydrolase I expression, protein, and activity determine intracellular tetrahydrobiopterin levels, independent of GTP cyclohydrolase feedback regulatory protein expression. J. Biol. Chem. 284, 13660–13668.

Wang, Q., Yang, M., Xu, H., and Yu, J. (2014). Tetrahydrobiopterin improves endothelial function in cardiovascular disease: a systematic review. Evid.-Based Complement. Altern. Med. ECAM 2014, 850312.

Whitsett, J., Picklo, M.J., and Vasquez-Vivar, J. (2007). 4-Hydroxy-2-nonenal increases superoxide anion radical in endothelial cells via stimulated GTP cyclohydrolase proteasomal degradation. Arterioscler. Thromb. Vasc. Biol. 27, 2340–2347.

Zhao Y, Cao J, Chen YS, Zhu Y, Patrick C, Chien B, Cheng A, Foehr ED.  Detection of tetrahydrobiopterin by LC-MS/MS in plasma from multiple species.  Bioanalysis. 2009;1(5):895-903.