Tetrahydrobiopterin

en.wikipedia.org /wiki/Tetrahydrobiopterin

Tetrahydrobiopterin

Clinical data

License data
US FDA: Kuvan

Pregnancy
category US: C (Risk not ruled out)

Routes of By mouth
administration

ATC code
A16AX07 (WHO)

Legal status

Legal status
US: -only

Pharmacokinetic data

Biological half-life 4 hours (healthy adults)

67 hours (PKU patients)

Identifiers

IUPAC name

CAS Number
17528-72-2

PubChem CID
44257

IUPHAR/BPS
5276

DrugBank
DB00360

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 ChemSpider
40270

ChEBI
CHEBI:59560

ChEMBL
CHEMBL1201774

Chemical and physical data

Formula C9H15N5O3

Molar mass 241.25 g/mol

3D model (JSmol)
Interactive image

SMILES

InChI

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Tetrahydrobiopterin (BH4, THB), also known as sapropterin, 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. [1] Chemically, its structure is that of a reduced pteridine derivative.

Medical use
Tetrahydrobiopterin is available as a tablet for oral administration in the form of tetrahydrobiopterin
dihydrochloride (BH4*2HCL). [2] BH4*2HCL is FDA approved under the trade name Kuvan. The typical cost of
treating a patient with Kuvan is $100,000 per year.[3] BioMarin holds the patent for Kuvan until at least 2024, but
Par Pharmaceutical has a right to produce a generic version by 2020. [4]

BH4*2HCL is indicated in tetrahydrobiopterin deficiency caused by GTPCH deficiency or PTPS deficiency. [5]
Also, BH4*2HCL is FDA approved for use in phenylketonuria, along with dietary measures.[6] Most people with
phenylketonuria, however, have little or no benefit of BH4*2HCL. [7]

Adverse effects
The most common adverse effects, observed in more than 10% of patients, include headache and a running or
obstructed nose. Diarrhea and vomiting are also relatively common, seen in at least 1% of patients. [8]

Interactions
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.[8]

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Functions
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, major monoamine
neurotransmitters. Due to its role in the conversion of L-tyrosine into 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;[9] 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.[10]

History
Tetrahydrobiopterin was discovered to play a role as an enzymatic cofactor. The first enzyme found to use
tetrahydrobiopterin is phenylalanine hydroxylase (PAH).[11]

Biosynthesis and recycling

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). [12]

BH4 is catabolized to BH3 and BH2, which are pro-oxidants (free radicals). Research shows that ascorbic acid
(also known as ascorbate or vitamin C) is effective at recycling BH3 into BH4, [13] preventing the BH3 radical
from reacting with other free radicals (superoxide and peroxynitrite specifically). Without this recycling process,
uncoupling of the endothelial nitric oxide synthase (eNOS) enzyme and reduced bioavailability of the vasodilator
nitric oxide occur, creating a form of endothelial dysfunction.[14] Ascorbic acid is oxidized to dehydroascorbic
acid during this process, although it can be recycled back to ascorbic acid.

Research
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.[15][16] 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. A 2015 BioMarin-funded study
of PKU patients found that those who responded to tetrahydrobiopterin also showed a reduction of ADHD
symptoms.[17]

Autism

In 1997, a small pilot study was published on the efficacy of tetrahydrobiopterin (BH4) on relieving the symptoms
of autism, which concluded that it "might be useful for a subgroup of children with autism" and that double-blind
trials are needed, as are trials which measure outcomes over a longer period of time.[18] In 2010, Frye et al.
published a paper which concluded that it was safe, and also noted that "several clinical trials have suggested

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that treatment with BH4 improves ASD symptomatology in some individuals."[19]

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.[20] 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,[21]
atherosclerosis, and hypoxic pulmonary hypertension. [22] However, treatment of patients with existing coronary
artery disease with oral tetrahydrobiopterin is limited by oxidation of tetrahydrobiopterin to the inactive form,
dihydrobiopterin, with little benefit on vascular function. [23]

See also

References
1. Jump up ^ Caka, Jarosaw (2006). "The role of nitric oxide in the hypothalamic control of LHRH and
oxytocin release, sexual behavior and aging of the LHRH and oxytocin neurons". Folia Histochemica et
Cytobiologica. 44 (1): 312. PMID 16584085.
2. Jump up ^ Schaub J, Dumling S, Curtius HC, Niederwieser A, Bartholom K, Viscontini M, Schircks B,
Bieri JH (1978). "Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin
biosynthesis". Arch. Dis. Child. 53 (8): 6746. PMC 1545051 . PMID 708106.
3. Jump up ^ Matthew Herper (2016-07-28). "How Focusing On Obscure Diseases Made BioMarin A $15
Billion Company". Forbes. Retrieved 2017-10-09.
4. Jump up ^ "BioMarin Announces Kuvan (sapropterin dihydrochloride) Patent Challenge Settlement" . PR
Newswire. 2017-04-13. Retrieved 2017-10-09.
5. Jump up ^ "Tetrahydrobiopterin Deficiency". National Organization for Rare Disorders (NORD).
Retrieved 2017-10-09.
6. Jump up ^ "What are common treatments for phenylketonuria (PKU)?". NICHD. 2013-08-23. Retrieved
12 September 2016.
7. Jump up ^ Camp, Kathryn M.; Parisi, Melissa A.; Acosta, Phyllis B.; Berry, Gerard T.; Bilder, Deborah A.;
Blau, Nenad; Bodamer, Olaf A.; Brosco, Jeffrey P.; Brown, Christine S.; Burlina, Alberto B.; Burton,
Barbara K.; Chang, Christine S.; Coates, Paul M.; Cunningham, Amy C.; Dobrowolski, Steven F.;
Ferguson, John H.; Franklin, Thomas D.; Frazier, Dianne M.; Grange, Dorothy K.; Greene, Carol L.; Groft,
Stephen C.; Harding, Cary O.; Howell, R. Rodney; Huntington, Kathleen L.; Hyatt-Knorr, Henrietta D.;
Jevaji, Indira P.; Levy, Harvey L.; Lichter-Konecki, Uta; Lindegren, Mary Lou; et al. (2014).
"Phenylketonuria Scientific Review Conference: State of the science and future research needs".
Molecular Genetics and Metabolism. 112 (2): 87122. doi:10.1016/j.ymgme.2014.02.013.
PMID 24667081.

8. ^ Jump up to: a b Haberfeld, H, ed. (1 March 2017). Austria-Codex (in German). Vienna: sterreichischer
Apothekerverlag. Kuvan 100 mg-Tabletten.
9. Jump up ^ "Genetics Home Reference: GCH1". National Institutes of Health.
10. Jump up ^ Wu, Guoyao; Meininger, Cynthia J. (2009). "Nitric oxide and vascular insulin resistance".
BioFactors. 35 (1): 217. doi:10.1002/biof.3. PMID 19319842.
11. Jump up ^ Kaufman, S (1958). "A new cofactor required for the enzymatic conversion of phenylalanine to
tyrosine". The Journal of Biological Chemistry. 230 (2): 9319. PMID 13525410.
12. Jump up ^ Thny, Beat; Auerbach, Gnter; Blau, Nenad (2000). "Tetrahydrobiopterin biosynthesis,
regeneration and functions". Biochemical Journal. 347: 116. doi:10.1042/0264-6021:3470001.
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 PMC 1220924 . PMID 10727395.
13. Jump up ^ Kuzkaya, N.; Weissmann, N.; Harrison, D. G.; Dikalov, S. (2003). "Interactions of
Peroxynitrite, Tetrahydrobiopterin, Ascorbic Acid, and Thiols: IMPLICATIONS FOR UNCOUPLING
ENDOTHELIAL NITRIC-OXIDE SYNTHASE". Journal of Biological Chemistry. 278 (25): 2254654.
doi:10.1074/jbc.M302227200. PMID 12692136.
14. Jump up ^ Muller-Delp, J. M. (2009). "Ascorbic acid and tetrahydrobiopterin: looking beyond nitric oxide
bioavailability". Cardiovascular Research. 84 (2): 1789. doi:10.1093/cvr/cvp307. PMID 19744948.
15. Jump up ^ ClinicalTrials.gov: Search results for Kuvan
16. Jump up ^ "BioMarin Initiates Phase 3b Study to Evaluate the Effects of Kuvan on Neurophychiatric
Symptoms in Subjects with PKU". BioMarin Pharmaceutical Inc. 17 August 2010.
17. Jump up ^ Burton, B.; Grant, M.; Feigenbaum, A.; Singh, R.; Hendren, R.; Siriwardena, K.; Phillips, J.;
Sanchez-Valle, A.; Waisbren, S.; Gillis, J.; Prasad, S.; Merilainen, M.; Lang, W.; Zhang, C.; Yu, S.; Stahl,
S. (2015). "A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms
and executive function impairment in children and adults with sapropterin-responsive phenylketonuria".
Molecular Genetics and Metabolism. 114 (3): 41524. doi:10.1016/j.ymgme.2014.11.011.
PMID 25533024.
18. Jump up ^ Fernell, Elisabeth; Watanabe, Yasuyoshi; Adolfsson, Ingrid; Tani, Yoshihiro; Bergstrm, Mats;
Phd, Per Hartvig; Md, Anders Lilja; Phd., Anne-Liis von Knorring MD.; Phd., Christopher Gillberg MD.;
Phd., Bengt Lngstrm (2008). "Possible effects of tetrahydrobiopterin treatment in six children with
autism - clinical and positron emission tomography data: A pilot study". Developmental Medicine & Child
Neurology. 39 (5): 3138. doi:10.1111/j.1469-8749.1997.tb07437.x. PMID 9236697.
19. Jump up ^ Frye, Richard E.; Huffman, Lynne C.; Elliott, Glen R. (2010). "Tetrahydrobiopterin as a novel
therapeutic intervention for autism". Neurotherapeutics. 7 (3): 2419. doi:10.1016/j.nurt.2010.05.004.
PMC 2908599 . PMID 20643376.
20. Jump up ^ Channon, Keithm. (2004). "Tetrahydrobiopterin". Trends in Cardiovascular Medicine. 14 (8):
3237. doi:10.1016/j.tcm.2004.10.003. PMID 15596110.
21. Jump up ^ Alp, Nicholas J.; Mussa, Shafi; Khoo, Jeffrey; Cai, Shijie; Guzik, Tomasz; Jefferson, Andrew;
Goh, Nicky; Rockett, Kirk A.; Channon, Keith M. (2003). "Tetrahydrobiopterin-dependent preservation of
nitric oxidemediated endothelial function in diabetes by targeted transgenic GTPcyclohydrolase I
overexpression". Journal of Clinical Investigation. 112 (5): 72535. doi:10.1172/JCI17786. PMC 182196
. PMID 12952921.
22. Jump up ^ Khoo, J. P.; Zhao, L; Alp, N. J.; Bendall, J. K.; Nicoli, T; Rockett, K; Wilkins, M. R.; Channon,
K. M. (2005). "Pivotal Role for Endothelial Tetrahydrobiopterin in Pulmonary Hypertension". Circulation.
111 (16): 212633. doi:10.1161/01.CIR.0000162470.26840.89. PMID 15824200.
23. Jump up ^ Cunnington, C.; Van Assche, T.; Shirodaria, C.; Kylintireas, I.; Lindsay, A. C.; Lee, J. M.;
Antoniades, C.; Margaritis, M.; Lee, R.; Cerrato, R.; Crabtree, M. J.; Francis, J. M.; Sayeed, R.;
Ratnatunga, C.; Pillai, R.; Choudhury, R. P.; Neubauer, S.; Channon, K. M. (2012). "Systemic and
Vascular Oxidation Limits the Efficacy of Oral Tetrahydrobiopterin Treatment in Patients with Coronary
Artery Disease". Circulation. 125 (11): 135666. doi:10.1161/CIRCULATIONAHA.111.038919.
PMC 5238935 . PMID 22315282.

External links
Coenzyme tetrahydrobiopterin (BH 4)
Information on phenylketunaria (PKU)

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