Tetrahydrobiopterin

Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN),[2][3] is a cofactor of the three aromatic amino acid hydroxylase enzymes,[4] 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.[5] Chemically, its structure is that of a reduced pteridine derivative.

Tetrahydrobiopterin
INN: sapropterin
Clinical data
Trade namesKuvan, Biopten
Other namesSapropterin hydrochloride (JAN JP), Sapropterin dihydrochloride (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa608020
License data
Pregnancy
category
    Routes of
    administration    		By mouth
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Elimination half-life4 hours (healthy adults)
    6–7 hours (PKU patients)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    PDB ligand
    CompTox Dashboard (EPA)
    ECHA InfoCard100.164.121
    Chemical and physical data
    FormulaC9H15N5O3
    Molar mass241.251 g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Medical use

    Tetrahydrobiopterin is available as a tablet for oral administration in the form of sapropterin dihydrochloride (BH4*2HCL).[6][7][8] It was approved for use in the United States as a tablet in December 2007[9][10] and as a powder in December 2013.[11][10] It was approved for use in the European Union in December 2008,[8], Canada in April 2010,[10] and Japan in July 2008.[10] It is sold under the brand names Kuvan and Biopten.[8][7][10] The typical cost of treating a patient with Kuvan is US$100,000 per year.[12] BioMarin holds the patent for Kuvan until at least 2024, but Par Pharmaceutical has a right to produce a generic version by 2020.[13]

    Sapropterin is indicated in tetrahydrobiopterin deficiency caused by GTP cyclohydrolase I (GTPCH) deficiency, or 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency.[14] Also, BH4*2HCL is FDA approved for use in phenylketonuria (PKU), along with dietary measures.[15] However, most people with PKU have little or no benefit from BH4*2HCL.[16]

    Adverse effects

    The most common adverse effects, observed in more than 10% of people, include headache and a running or obstructed nose. Diarrhea and vomiting are also relatively common, seen in at least 1% of people.[17]

    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.[17]

    Functions

    Tetrahydrobiopterin has multiple roles in human biochemistry. The major one is to convert amino acids such as phenylalanine, tyrosine, and tryptophan to precursors of dopamine and serotonin, major monoamine neurotransmitters. It works as a cofactor, being required for an enzyme's activity as a catalyst, mainly hydroxylases.[4]

    Cofactor for tryptophan hydroxylases
    Further information: Tryptophan hydroxylase

    Tetrahydrobiopterin is a cofactor for tryptophan hydroxylase (TPH) for the conversion of L-tryptophan (TRP) to 5-hydroxytryptophan (5-HTP).

    Cofactor for phenylalanine hydroxylase

    Phenylalanine hydroxylase (PAH) catalyses the conversion of L-phenylalanine (PHE) to L-tyrosine (TYR). Therefore, a deficiency in tetrahydrobiopterin can cause severe neurological issues related to a toxic buildup of L-phenylalanine.

    Cofactor for tyrosine hydroxylase

    Tyrosine hydroxylase (TH) catalyses the conversion of L-tyrosine to L-DOPA (DOPA), which is the precursor for dopamine. 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;[18] currently, this condition is typically treated with carbidopa/levodopa, which directly restores dopamine levels within the brain.

    Cofactor for nitric oxide synthase

    Nitric oxide synthase (NOS) catalyses the conversion of a guanidino nitrogen of L-arginine (L-Arg) to nitric oxide (NO). 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.[19]

    Cofactor for ether lipid oxidase

    Ether lipid oxidase (Alkylglycerol monooxygenase, AGMO) catalyses the conversion of 1-alkyl-sn-glycerol to 1-hydroxyalkyl-sn-glycerol.

    History

    Tetrahydrobiopterin was discovered to play a role as an enzymatic cofactor. The first enzyme found to use tetrahydrobiopterin is phenylalanine hydroxylase (PAH).[20]

    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).[21]

    BH4 can be oxidized by one or two electron reactions, to generate BH4 or BH3 radical and BH2, respectively. Research shows that ascorbic acid (also known as ascorbate or vitamin C) can reduce BH3 radical into BH4,[22] 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.[23] Ascorbic acid is oxidized to dehydroascorbic acid during this process, although it can be recycled back to ascorbic acid.

    Folic acid and its metabolites seem to be particularly important in the recycling of BH4 and NOS coupling.[24]

    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.[25][26] 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.[27]

    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.[28] In 2010, Frye et al. published a paper which concluded that it was safe, and also noted that "several clinical trials have suggested that treatment with BH4 improves ASD symptomatology in some individuals."[29]

    Cardiovascular disease

    Since nitric oxide 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 nitric oxide synthase is dependent on tetrahydrobiopterin availability.[30] Increasing tetrahydrobiopterin in endothelial cells by augmenting the levels of the biosynthetic enzyme GTPCH can maintain endothelial nitric oxide synthase function in experimental models of disease states such as diabetes,[31] atherosclerosis, and hypoxic pulmonary hypertension.[32] However, treatment of people 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.[33]

    Neuroprotection in prenatal hypoxia

    Depletion of tetrahydrobiopterin occurs in the hypoxic brain and leads to toxin production. Preclinical studies in mice reveal that treatment with oral tetrahydrobiopterin therapy mitigates the toxic effects of hypoxia on the developing brain, specifically improving white matter development in hypoxic animals.[34]

    See also

    References
    1. "Sapropterin (Kuvan) Use During Pregnancy". Drugs.com. 17 May 2019. Retrieved 4 March 2020.
    2. "Sapropterin". Drugs.com. 28 February 2020. Retrieved 4 March 2020.
    3. "International Non-proprietary Names for Pharmaceutical Substances (INN)". Fimea. Retrieved 4 March 2020.
    4. Kappock, T. Joseph; Caradonna, John P. (1996). "Pterin-Dependent Amino Acid Hydroxylases". Chemical Reviews. 96 (7): 2659–2756. doi:10.1021/CR9402034. PMID 11848840.CS1 maint: uses authors parameter (link)
    5. Całka, Jarosław (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): 3–12. PMID 16584085.
    6. Schaub J, Däumling S, Curtius HC, Niederwieser A, Bartholomé K, Viscontini M, Schircks B, Bieri JH (1978). "Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis". Arch. Dis. Child. 53 (8): 674–6. doi:10.1136/adc.53.8.674. PMC 1545051. PMID 708106.
    7. "Kuvan- sapropterin dihydrochloride tablet Kuvan- sapropterin dihydrochloride powder, for solution Kuvan- sapropterin dihydrochloride powder, for solution". DailyMed. 13 December 2019. Retrieved 4 March 2020.
    8. "Kuvan EPAR". European Medicines Agency (EMA). 4 March 2020. Retrieved 4 March 2020.
    9. "Drug Approval Package: Kuvan (Sapropterin Dihydrochloride) NDA #022181". U.S. Food and Drug Administration (FDA). 24 March 2008. Retrieved 4 March 2020. Lay summary (PDF).
    10. "Kuvan (sapropterin dihydrochloride) Tablets and Powder for Oral Solution for PKU". BioMarin. Retrieved 4 March 2020.
    11. "Drug Approval Package: Kuvan Powder for Oral Solution (Sapropterin Dihydrochloride) NDA #205065". U.S. Food and Drug Administration (FDA). 28 February 2014. Retrieved 4 March 2020. Lay summary (PDF).
    12. Herper, Matthew (28 July 2016). "How Focusing On Obscure Diseases Made BioMarin A $15 Billion Company". Forbes. Retrieved 9 October 2017.
    13. "BioMarin Announces Kuvan (sapropterin dihydrochloride) Patent Challenge Settlement". BioMarin Pharmaceutical Inc. 13 April 2017. Retrieved 9 October 2017 – via PR Newswire.
    14. "Tetrahydrobiopterin Deficiency". National Organization for Rare Disorders (NORD). Retrieved 9 October 2017.
    15. "What are common treatments for phenylketonuria (PKU)?". NICHD. 23 August 2013. Retrieved 12 September 2016.
    16. Camp, Kathryn M.; Parisi, Melissa A.; Acosta, Phyllis B.; et al. (2014). "Phenylketonuria Scientific Review Conference: State of the science and future research needs". Molecular Genetics and Metabolism. 112 (2): 87–122. doi:10.1016/j.ymgme.2014.02.013. PMID 24667081.
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    18. "Genetics Home Reference: GCH1". National Institutes of Health.
    19. Wu, Guoyao; Meininger, Cynthia J. (2009). "Nitric oxide and vascular insulin resistance". BioFactors. 35 (1): 21–7. doi:10.1002/biof.3. PMID 19319842.
    20. Kaufman, S (1958). "A new cofactor required for the enzymatic conversion of phenylalanine to tyrosine". The Journal of Biological Chemistry. 230 (2): 931–9. PMID 13525410.
    21. Thöny, Beat; Auerbach, Günter; Blau, Nenad (2000). "Tetrahydrobiopterin biosynthesis, regeneration and functions". Biochemical Journal. 347: 1–16. doi:10.1042/0264-6021:3470001. PMC 1220924. PMID 10727395.
    22. 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): 22546–54. doi:10.1074/jbc.M302227200. PMID 12692136.
    23. Muller-Delp, J. M. (2009). "Ascorbic acid and tetrahydrobiopterin: looking beyond nitric oxide bioavailability". Cardiovascular Research. 84 (2): 178–9. doi:10.1093/cvr/cvp307. PMID 19744948.
    24. Gori, Tommaso; Burstein, Jason M.; Ahmed, Sofia; Miner, Steve E.S.; Al-Hesayen, Abdul; Kelly, Susan; Parker, John D. (4 September 2001). "Folic Acid Prevents Nitroglycerin-Induced Nitric Oxide Synthase Dysfunction and Nitrate Tolerance: A Human In Vivo Study". Circulation. 104 (10): 1119–1123. doi:10.1161/hc3501.095358. ISSN 0009-7322. PMID 11535566.
    25. ClinicalTrials.gov: Search results for Kuvan
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    33. 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): 1356–66. doi:10.1161/CIRCULATIONAHA.111.038919. PMC 5238935. PMID 22315282.
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    Further reading
    • "Sapropterin". Drug Information Portal. U.S. National Library of Medicine.
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