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Event Title

Tetrahydrobiopterin, Decrease

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Oxidative Stress Leading to Hypertension KE Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
Homo sapiens Homo sapiens Moderate NCBI
Bos taurus Bos taurus Strong NCBI
Mus musculus Mus musculus Strong NCBI
Rattus norvegicus Rattus norvegicus Weak NCBI

Level of Biological Organization

Biological Organization

How this Key Event works

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 is 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

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).

Evidence Supporting Taxonomic Applicability

Decreased BH4 is observed in humans (Jayaram et al., 2015), cows (Ismail et al., 2015; 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).


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.

Ismail, R., Elmahdy, M., AbdelGhany, T., Lowe, F., and Zweier, J. (2015). Cigarette smoke constituents cause endothelial dysfunction due to oxidative depletion of tetrahydrobiopterin and activation of the ubiquitin proteasome system. Free Radic. Biol. Med. Under review.

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.