Systematic (IUPAC) name
Clinical data
Licence data US FDA:link
Pregnancy cat. C(US)
Legal status -only (US)
Routes Oral
Pharmacokinetic data
Half-life 4 hours (healthy adults)
6–7 hours (PKU patients)
CAS number 17528-72-2 YesY
ATC code A16AX07
PubChem CID 44257
DrugBank DB00360
ChemSpider 40270 YesY
Chemical data
Formula C9H15N5O3 
Mol. mass 241.25 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Tetrahydrobiopterin (BH4, THB, trade name Kuvan) or sapropterin (INN) is a naturally occurring essential cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases.[citation needed]



Tetrahydrobiopterin was discovered to play a role as an enzymatic cofactor. The first enzyme found to use tetrahydrobiopterin is phenylalanine hydroxylase (PAH).[1]


Tetrahydrobiopterin is biosynthesized from guanosine triphosphate (GTP) by three chemical reactions mediated by the enzymes GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin reductase (SR).[2]


Tetrahydrobiopterin has the following responsibilities as a cofactor:

Tetrahydrobiopterin has multiple roles in human biochemistry. One is to convert amino acids such as phenylalanine, tyrosine, and tryptophan to precursors of dopamine and serotonin, the body's primary neurotransmitters). Due to its role in the conversion of L-tyrosine in to L-dopa, which is the precursor for dopamine. A deficiency in tetrahydrobiopterin can cause severe neurological issues unrelated to a toxic buildup of L-phenylalanine; dopamine is a vital neurotransmitter, and is the precursor of norepinephrine and epinephrine. Thus, a deficiency of BH4 can lead to systemic deficiencies of dopamine, norepinephrine, and epinephrine. In fact, one of the primary conditions that can result from GTPCH-related BH4 deficiency is dopamine-responsive dystonia;[3] currently, this condition is typically treated with carbidopa/levodopa, which directly restores dopamine levels within the brain.

BH4 also serves as a catalyst for the production of nitric oxide. Among other things, nitric oxide is involved in vasodilation, which improves systematic blood flow. The role of BH4 in this enzymatic process is so critical that some research points to a deficiency of BH4 – and thus, of nitric oxide – as being a core cause of the neurovascular dysfunction that is the hallmark of circulation-related diseases such as diabetes.[4]

Clinical usage


A deficit in tetrahydrobiopterin biosynthesis and/or regeneration can result in phenylketonuria (PKU) from excess L-phenylalanine concentrations or hyperphenylalaninemia (HPA), as well as monoamine and nitric oxide neurotransmitter deficiency or chemical imbalance. The chronic presence of PKU can result in severe brain damage, including symptoms of mental retardation, microcephaly, speech impediments such as stuttering, slurring, and lisps, seizures or convulsions, and behavioral abnormalities, among other effects.

Tetrahydrobiopterin, developed by BioMarin under the brand name Kuvan and approved by the United States (U.S.) Food and Drug Administration (FDA) on December 13, 2007 and European Medicines Agency (EMA) in 2008, is a synthetic preparation of the dihydrochloride salt of the substance containing ascorbic acid, used in the treatment of PKU and tetrahydrobiopterin deficiencies.[5] Sapropterin is the first non-dietary treatment for patients with PKU that has been shown in randomized, double-blind trials to be effective in lowering blood phenylalanine levels.[6]

Cardiovascular disease

Since NO production is important in regulation of blood pressure and blood flow, thereby playing a significant role in cardiovascular diseases, tetrahydrobiopterin is a potential therapeutic target. In the endothelial cell lining of blood vessels, endothelial NOS is dependent on tetrahydrobiopterin availability.[7] Increasing tetrahydrobiopterin in endothelial cells by augmenting the levels of the biosynthetic enzyme GTPCH can maintain endothelial NOS function in experimental models of disease states such as diabetes,[8] atherosclerosis, and hypoxic pulmonary hypertension.[9]

Tetrahydrobiopterin may be of benefit in the management and treatment of intractable diastolic heart failure, based on research in mice. There are fewer ways to manage systolic heart failure than for diastolic heart failure.[10]


Other than PKU studies, tetrahydrobiopterin has participated in clinical trials studying other approaches to solving conditions resultant from a deficiency of tetrahydrobiopterin. These include autism, ADHD, hypertension, endothelial dysfunction, and chronic kidney disease.[11][12] As of September 2010, no results are available. Experimental studies suggest that tetrahydrobiopterin regulates deficient production of nitric oxide in cardiovascular disease states, and contributes to the response to inflammation and injury, for example in pain due to nerve injury.

Adverse effects

The most common adverse effects, observed in more than 10% of patients, include headache and a running or obstructed nose. Diahrrhea and vomiting are also relatively common, seen in at least 1% of patients.[13]


No interaction studies have been conducted. Because of its mechanism, tetrahydrobiopterin might interact with dihydrofolate reductase inhibitors like methotrexate and trimethoprim, and NO-enhancing drugs like nitroglycerin, molsidomine, minoxidil, and PDE5 inhibitors. Combination of tetrahydrobiopterin with levodopa can lead to increased excitability.[13]

See also


  1. ^ Kaufman, S (1 February 1958). "A New Cofactor Required for the Enzymatic Conversion of Phenylalanine to Tyrosine.". J. Biol. Chem. 230 (2): 931–939. PMID 13525410. http://www.jbc.org/cgi/reprint/230/2/931. 
  2. ^ Thony B, Auerbach G, Blau N (2000). "Tetrahydrobiopterin Biosynthesis, Regeneration and Functions.". Biochem J 347 Pt. 1: 1–16. doi:10.1042/0264-6021:3470001. PMC 1220924. PMID 10727395. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1220924. 
  3. ^ "Genetics Home Reference: GCH1". National Institutes of Health. http://ghr.nlm.nih.gov/gene/GCH1. 
  4. ^ . PMID 19319842. 
  5. ^ Barbara K. Burton, Santwana Kar & Peter Kirkpatrick (2008). "Fresh from the Pipeline: Sapropterin.". Nature Reviews Drug Discovery 7 (3): 199–200. doi:10.1038/nrd2540. 
  6. ^ Sanford, Mark; Keating, Gillian M. (2009). "Sapropterin". Drugs 69 (4): 461. doi:10.2165/00003495-200969040-00006. PMID 19323589. http://adisonline.com/drugs/abstract/2009/69040/Sapropterin__A_Review_of_its_Use_in_the_Treatment.6.aspx. 
  7. ^ Channon KM. (2004). "Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease.". Trends Cardiovasc Med 14: 823–827. PMID 15596110. 
  8. ^ Alp NJ et al. (2003). "Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression.". J Clin Invest 112: 725–735. doi:10.1172/JCI17786. PMC 182196. PMID 12952921. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=182196. 
  9. ^ Khoo J et al. (2005). "Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension.". Circulation 111: 2126–2133. PMID 15824200. 
  10. ^ Gad A. Silberman, Tai-Hwang M. Fan, Hong Liu, Zhe Jiao, Hong D. Xiao, Joshua D Lovelock, Beth M. Boulden, Julian Widder, Scott Fredd, Kenneth E. Bernstein, Beata M. Wolska, Sergey Dikalov, David G. Harrison and Samuel C. Dudley, Jr. (2010). "Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction". Circulation 121 (4): 519–528. doi:10.1161/CIRCULATIONAHA.109.883777. PMC 2819317. PMID 20083682. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2819317. 
  11. ^ ClinicalTrials.gov: Search results for Kuvan
  12. ^ "BioMarin Initiates Phase 3b Study to Evaluate the Effects of Kuvan on Neurophychiatric Symptoms in Subjects with PKU". BioMarin Pharmaceutical Inc. 17 August 2010. http://www.fiercebiotech.com/press-releases/biomarin-initiates-phase-3b-study-evaluate-effects-kuvan-neurophychiatric-symptoms-su. 
  13. ^ a b Haberfeld, H, ed (2009) (in German). Austria-Codex (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X. 

External links

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