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Tetrahydrobiopterin

August 29, 2023

"BH4" redirects here. For the anion, see Borohydride.

Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN),[5][6] is a cofactor of the three aromatic amino acid hydroxylase enzymes,[7] 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.[8][9] Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin).[10][citation needed]

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
  • (6R)-2-Amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydropteridin-4(1H)-one
CAS Number
  • 62989-33-7 Y
  • as salt: 69056-38-8
PubChem CID
  • 135398654
IUPHAR/BPS
  • 5276
DrugBank
  • DB00360 Y
  • as salt: DBSALT001133
ChemSpider
  • 40270 Y
  • as salt: 552166
UNII
  • EGX657432I
KEGG
  • D08505
  • as salt: D01798
ChEBI
  • CHEBI:59560 Y
  • as salt: CHEBI:32120
ChEMBL
  • ChEMBL1201774 N
  • as salt: ChEMBL1201775
PDB ligand
  • H4B (PDBe, RCSB PDB)
CompTox Dashboard (EPA)
  • DTXSID1041138
ECHA InfoCard100.164.121
Chemical and physical data
FormulaC9H15N5O3
Molar mass241.251 g·mol−1
3D model (JSmol)
  • Interactive image
  • CC(C(C1CNC2=C(N1)C(=O)N=C(N2)N)O)O
  • InChI=1S/C9H15N5O3/c1-3(15)6(16)4-2-11-7-5(12-4)8(17)14-9(10)13-7/h3-4,6,12,15-16H,2H2,1H3,(H4,10,11,13,14,17)/t3-,4+,6-/m0/s1 Y
  • Key:FNKQXYHWGSIFBK-RPDRRWSUSA-N Y
 NY (what is this?)  (verify)

Medical use Edit

Tetrahydrobiopterin is available as a tablet for oral administration in the form of sapropterin dihydrochloride (BH4*2HCL).[11][3][4] It was approved for use in the United States as a tablet in December 2007[12][13] and as a powder in December 2013.[14][13] It was approved for use in the European Union in December 2008,[4] Canada in April 2010,[2] and Japan in July 2008.[13] It is sold under the brand names Kuvan and Biopten.[4][3][13] The typical cost of treating a patient with Kuvan is US$100,000 per year.[15] BioMarin holds the patent for Kuvan until at least 2024, but Par Pharmaceutical has a right to produce a generic version by 2020.[16]

Sapropterin is indicated in tetrahydrobiopterin deficiency caused by GTP cyclohydrolase I (GTPCH) deficiency, or 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency.[17] Also, BH4*2HCL is FDA approved for use in phenylketonuria (PKU), along with dietary measures.[18] However, most people with PKU have little or no benefit from BH4*2HCL.[19]

Adverse effects Edit

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.[20]

Interactions Edit

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.[20]

Functions Edit

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.[21] It works as a cofactor, being required for an enzyme's activity as a catalyst, mainly hydroxylases.[7]

Cofactor for tryptophan hydroxylases Edit

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 Edit

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

Cofactor for tyrosine hydroxylase Edit

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;[22] currently, this condition is typically treated with carbidopa/levodopa, which directly restores dopamine levels within the brain.

Cofactor for nitric oxide synthase Edit

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.[23]

Cofactor for ether lipid oxidase Edit

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

History Edit

Tetrahydrobiopterin was discovered to play a role as an enzymatic cofactor. The first enzyme found to use tetrahydrobiopterin is phenylalanine hydroxylase (PAH).[24]

Biosynthesis and recycling Edit

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).[25]

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,[26] 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.[27] 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.[28]

Research Edit

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, depression,[29] ADHD, hypertension, endothelial dysfunction, and chronic kidney disease.[30][31] 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.[32]

Depression Edit

In psychiatry, tetrahydrobiopterin has been hypothesized to be involved in the pathophysiology of depression, although evidence is inconclusive to date.[33]

Autism Edit

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.[34] 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."[35]

Cardiovascular disease Edit

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.[36] 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,[37] atherosclerosis, and hypoxic pulmonary hypertension.[38] 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.[39]

Neuroprotection in prenatal hypoxia Edit

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.[40]

Programmed cell death Edit

GTPCH (GCH1) and tetrahydrobiopterin were found to have a secondary role protecting against cell death by ferroptosis in cellular models by limiting the formation of toxic lipid peroxides.[41] Tetrahydrobiopterin acts as a potent, diffusable antioxidant that resists oxidative stress[42] and enables cancer cell survival via promotion of angiogenesis.[43]

References Edit

  1. ^ "Sapropterin (Kuvan) Use During Pregnancy". Drugs.com. 17 May 2019. Retrieved 4 March 2020.
  2. ^ a b "Kuvan Product information". Health Canada. 25 April 2012. Retrieved 24 June 2022.
  3. ^ a b c "Kuvan- sapropterin dihydrochloride tablet Kuvan- sapropterin dihydrochloride powder, for solution Kuvan- sapropterin dihydrochloride powder, for solution". DailyMed. 13 December 2019. Retrieved 4 March 2020.
  4. ^ a b c d "Kuvan EPAR". European Medicines Agency (EMA). 4 March 2020. Retrieved 4 March 2020.
  5. ^ "Sapropterin". Drugs.com. 28 February 2020. Retrieved 4 March 2020.
  6. ^ "International Non-proprietary Names for Pharmaceutical Substances (INN)". Fimea. Retrieved 4 March 2020.
  7. ^ a b Kappock TJ, Caradonna JP (November 1996). "Pterin-Dependent Amino Acid Hydroxylases". Chemical Reviews. 96 (7): 2659–2756. doi:10.1021/CR9402034. PMID 11848840.
  8. ^ Cavaleri et al. Blood concentrations of neopterin and biopterin in subjects with depression: A systematic review and meta-analysis Progress in Neuro-Psychopharmacology and Biological Psychiatry 2023. 120:110633. http://dx.doi.org/10.1016/j.pnpbp.2022.110633
  9. ^ Całka J (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.
  10. ^ Bhagavan NV (2015). Essentials of Medical Biochemistry With Clinical Cases, 2nd Edition. USA: Elsevier. p. 256. ISBN 978-0-12-416687-5.
  11. ^ Schaub J, Däumling S, Curtius HC, Niederwieser A, Bartholomé K, Viscontini M, et al. (August 1978). "Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis". Archives of Disease in Childhood. 53 (8): 674–6. doi:10.1136/adc.53.8.674. PMC 1545051. PMID 708106.
  12. ^ "Drug Approval Package: Kuvan (Sapropterin Dihydrochloride) NDA #022181". U.S. Food and Drug Administration (FDA). 24 March 2008. Retrieved 4 March 2020.
    • Lay summary in: Daniel A. Shames (13 December 2007). "Summary Review: Application number: 22-181" (PDF). U.S. Food and Drug Administration.
  13. ^ a b c d "Kuvan (sapropterin dihydrochloride) Tablets and Powder for Oral Solution for PKU". BioMarin. Retrieved 4 March 2020.
  14. ^ "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.
  15. ^ Herper M (28 July 2016). "How Focusing On Obscure Diseases Made BioMarin A $15 Billion Company". Forbes. Retrieved 9 October 2017.
  16. ^ "BioMarin Announces Kuvan (sapropterin dihydrochloride) Patent Challenge Settlement". BioMarin Pharmaceutical Inc. 13 April 2017. Retrieved 9 October 2017 – via PR Newswire.
  17. ^ "Tetrahydrobiopterin Deficiency". National Organization for Rare Disorders (NORD). Retrieved 9 October 2017.
  18. ^ "What are common treatments for phenylketonuria (PKU)?". NICHD. 23 August 2013. Retrieved 12 September 2016.
  19. ^ Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, et al. (June 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.
  20. ^ a b Haberfeld, H, ed. (1 March 2017). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Kuvan 100 mg-Tabletten.
  21. ^ Cavaleri et al. Blood concentrations of neopterin and biopterin in subjects with depression: A systematic review and meta-analysis Progress in Neuro-Psychopharmacology and Biological Psychiatry 2023. 120:110633. http://dx.doi.org/10.1016/j.pnpbp.2022.110633
  22. ^ "Genetics Home Reference: GCH1". National Institutes of Health.
  23. ^ Wu G, Meininger CJ (2009). "Nitric oxide and vascular insulin resistance". BioFactors. 35 (1): 21–7. doi:10.1002/biof.3. PMID 19319842. S2CID 29828656.
  24. ^ Kaufman S (February 1958). "A new cofactor required for the enzymatic conversion of phenylalanine to tyrosine" (PDF). The Journal of Biological Chemistry. 230 (2): 931–9. doi:10.1016/S0021-9258(18)70516-4. PMID 13525410.
  25. ^ Thöny B, Auerbach G, Blau N (April 2000). "Tetrahydrobiopterin biosynthesis, regeneration and functions". The Biochemical Journal. 347 (Pt 1): 1–16. doi:10.1042/0264-6021:3470001. PMC 1220924. PMID 10727395.
  26. ^ Kuzkaya N, Weissmann N, Harrison DG, Dikalov S (June 2003). "Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase". The Journal of Biological Chemistry. 278 (25): 22546–54. doi:10.1074/jbc.M302227200. PMID 12692136.
  27. ^ Muller-Delp JM (November 2009). "Ascorbic acid and tetrahydrobiopterin: looking beyond nitric oxide bioavailability". Cardiovascular Research. 84 (2): 178–9. doi:10.1093/cvr/cvp307. PMID 19744948.
  28. ^ Gori T, Burstein JM, Ahmed S, Miner SE, Al-Hesayen A, Kelly S, Parker JD (September 2001). "Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study". Circulation. 104 (10): 1119–23. doi:10.1161/hc3501.095358. PMID 11535566.
  29. ^ Cavaleri et al. Blood concentrations of neopterin and biopterin in subjects with depression: A systematic review and meta-analysis Progress in Neuro-Psychopharmacology and Biological Psychiatry 2023. 120:110633. http://dx.doi.org/10.1016/j.pnpbp.2022.110633
  30. ^ "Search results for Kuvan". ClinicalTrials.gov. U.S. National Library of Medicine.
  31. ^ "BioMarin Initiates Phase 3b Study to Evaluate the Effects of Kuvan on Neurophychiatric Symptoms in Subjects with PKU". BioMarin Pharmaceutical Inc. 17 August 2010.
  32. ^ Burton B, Grant M, Feigenbaum A, Singh R, Hendren R, Siriwardena K, et al. (March 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): 415–24. doi:10.1016/j.ymgme.2014.11.011. PMID 25533024.
  33. ^ Cavaleri et al. Blood concentrations of neopterin and biopterin in subjects with depression: A systematic review and meta-analysis Progress in Neuro-Psychopharmacology and Biological Psychiatry 2023. 120:110633. http://dx.doi.org/10.1016/j.pnpbp.2022.110633
  34. ^ Fernell E, Watanabe Y, Adolfsson I, Tani Y, Bergström M, Hartvig P, et al. (May 1997). "Possible effects of tetrahydrobiopterin treatment in six children with autism--clinical and positron emission tomography data: a pilot study". Developmental Medicine and Child Neurology. 39 (5): 313–8. doi:10.1111/j.1469-8749.1997.tb07437.x. PMID 9236697. S2CID 12761124.
  35. ^ Frye RE, Huffman LC, Elliott GR (July 2010). "Tetrahydrobiopterin as a novel therapeutic intervention for autism". Neurotherapeutics. 7 (3): 241–9. doi:10.1016/j.nurt.2010.05.004. PMC 2908599. PMID 20643376.
  36. ^ Channon KM (November 2004). "Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease". Trends in Cardiovascular Medicine. 14 (8): 323–7. doi:10.1016/j.tcm.2004.10.003. PMID 15596110.
  37. ^ Alp NJ, Mussa S, Khoo J, Cai S, Guzik T, Jefferson A, et al. (September 2003). "Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression". The Journal of Clinical Investigation. 112 (5): 725–35. doi:10.1172/JCI17786. PMC 182196. PMID 12952921.
  38. ^ Khoo JP, Zhao L, Alp NJ, Bendall JK, Nicoli T, Rockett K, et al. (April 2005). "Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension". Circulation. 111 (16): 2126–33. doi:10.1161/01.CIR.0000162470.26840.89. PMID 15824200.
  39. ^ Cunnington C, Van Assche T, Shirodaria C, Kylintireas I, Lindsay AC, Lee JM, et al. (March 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.
  40. ^ Romanowicz J, Leonetti C, Dhari Z, Korotcova L, Ramachandra SD, Saric N, et al. (August 2019). "Treatment With Tetrahydrobiopterin Improves White Matter Maturation in a Mouse Model for Prenatal Hypoxia in Congenital Heart Disease". Journal of the American Heart Association. 8 (15): e012711. doi:10.1161/JAHA.119.012711. PMC 6761654. PMID 31331224.
  41. ^ Kraft VA, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, et al. (January 2020). "GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling". ACS Central Science. 6 (1): 41–53. doi:10.1021/acscentsci.9b01063. PMC 6978838. PMID 31989025.
  42. ^ Soula M, Weber RA, Zilka O, Alwaseem H, La K, Yen F, et al. (December 2020). "Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers". Nature Chemical Biology. 16 (12): 1351–1360. doi:10.1038/s41589-020-0613-y. PMC 8299533. PMID 32778843.
  43. ^ Chen L, Zeng X, Wang J, Briggs SS, O'Neill E, Li J, et al. (November 2010). "Roles of tetrahydrobiopterin in promoting tumor angiogenesis". The American Journal of Pathology. 177 (5): 2671–2680. doi:10.2353/ajpath.2010.100025. PMC 2966821. PMID 20847284.

Further reading Edit

  • "Clinical Review Report: Sapropterin dihydrochloride (Kuvan)". CADTH Common Drug Reviews. Ottawa, Canada: Canadian Agency for Drugs and Technologies in Health (CADTH). September 2017. PMID 30462435. Bookshelf ID: NBK533813.
  • Blau N (June 2016). "Genetics of Phenylketonuria: Then and Now". Human Mutation. 37 (6): 508–15. doi:10.1002/humu.22980. PMID 26919687.
  • Dubois EA, Cohen AF (June 2010). "Sapropterin". British Journal of Clinical Pharmacology. 69 (6): 576–7. doi:10.1111/j.1365-2125.2010.03643.x. PMC 2883749. PMID 20565448.
  • Muntau AC, Adams DJ, Bélanger-Quintana A, Bushueva TV, Cerone R, Chien YH, et al. (May 2019). "International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria". Molecular Genetics and Metabolism. 127 (1): 1–11. doi:10.1016/j.ymgme.2019.04.004. PMID 31103398.
  • Qu J, Yang T, Wang E, Li M, Chen C, Ma L, et al. (May 2019). "Efficacy and safety of sapropterin dihydrochloride in patients with phenylketonuria: A meta-analysis of randomized controlled trials". British Journal of Clinical Pharmacology. 85 (5): 893–899. doi:10.1111/bcp.13886. PMC 6475685. PMID 30720885.
  • van Wegberg AM, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, et al. (October 2017). "The complete European guidelines on phenylketonuria: diagnosis and treatment". Orphanet Journal of Rare Diseases. 12 (1): 162. doi:10.1186/s13023-017-0685-2. PMC 5639803. PMID 29025426.

External links Edit

  • "Sapropterin". Drug Information Portal. U.S. National Library of Medicine.
  • "Sapropterin dihydrochloride". Drug Information Portal. U.S. National Library of Medicine.

August 29, 2023
tetrahydrobiopterin, redirects, here, anion, borohydride, also, known, sapropterin, cofactor, three, aromatic, amino, acid, hydroxylase, enzymes, used, degradation, amino, acid, phenylalanine, biosynthesis, neurotransmitters, serotonin, hydroxytryptamine, mela. BH4 redirects here For the anion see Borohydride Tetrahydrobiopterin BH4 THB also known as sapropterin INN 5 6 is a cofactor of the three aromatic amino acid hydroxylase enzymes 7 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 8 9 Chemically its structure is that of a dihydropteridine reductase reduced pteridine derivative quinonoid dihydrobiopterin 10 citation needed TetrahydrobiopterinINN sapropterinClinical dataTrade namesKuvan BioptenOther namesSapropterin hydrochloride JAN JP Sapropterin dihydrochloride USAN US AHFS Drugs comMonographMedlinePlusa608020License dataEU EMA by INN US DailyMed Sapropterin US FDA SapropterinPregnancycategoryAU B1 1 Routes ofadministrationBy mouthATC codeA16AX07 WHO Legal statusLegal statusAU S4 Prescription only CA only 2 US only 3 EU Rx only 4 In general Prescription only Pharmacokinetic dataElimination half life4 hours healthy adults 6 7 hours PKU patients IdentifiersIUPAC name 6R 2 Amino 6 1R 2S 1 2 dihydroxypropyl 5 6 7 8 tetrahydropteridin 4 1H oneCAS Number62989 33 7 Yas salt 69056 38 8PubChem CID135398654IUPHAR BPS5276DrugBankDB00360 Yas salt DBSALT001133ChemSpider40270 Yas salt 552166UNIIEGX657432IKEGGD08505as salt D01798ChEBICHEBI 59560 Yas salt CHEBI 32120ChEMBLChEMBL1201774 Nas salt ChEMBL1201775PDB ligandH4B PDBe RCSB PDB CompTox Dashboard EPA DTXSID1041138ECHA InfoCard100 164 121Chemical and physical dataFormulaC 9H 15N 5O 3Molar mass241 251 g mol 13D model JSmol Interactive imageSMILES CC C C1CNC2 C N1 C O N C N2 N O OInChI InChI 1S C9H15N5O3 c1 3 15 6 16 4 2 11 7 5 12 4 8 17 14 9 10 13 7 h3 4 6 12 15 16H 2H2 1H3 H4 10 11 13 14 17 t3 4 6 m0 s1 YKey FNKQXYHWGSIFBK RPDRRWSUSA N Y N Y what is this verify Contents 1 Medical use 2 Adverse effects 3 Interactions 4 Functions 4 1 Cofactor for tryptophan hydroxylases 4 2 Cofactor for phenylalanine hydroxylase 4 3 Cofactor for tyrosine hydroxylase 4 4 Cofactor for nitric oxide synthase 4 5 Cofactor for ether lipid oxidase 5 History 6 Biosynthesis and recycling 7 Research 7 1 Depression 7 2 Autism 7 3 Cardiovascular disease 7 4 Neuroprotection in prenatal hypoxia 7 5 Programmed cell death 8 References 9 Further reading 10 External linksMedical use EditTetrahydrobiopterin is available as a tablet for oral administration in the form of sapropterin dihydrochloride BH4 2HCL 11 3 4 It was approved for use in the United States as a tablet in December 2007 12 13 and as a powder in December 2013 14 13 It was approved for use in the European Union in December 2008 4 Canada in April 2010 2 and Japan in July 2008 13 It is sold under the brand names Kuvan and Biopten 4 3 13 The typical cost of treating a patient with Kuvan is US 100 000 per year 15 BioMarin holds the patent for Kuvan until at least 2024 but Par Pharmaceutical has a right to produce a generic version by 2020 16 Sapropterin is indicated in tetrahydrobiopterin deficiency caused by GTP cyclohydrolase I GTPCH deficiency or 6 pyruvoyltetrahydropterin synthase PTPS deficiency 17 Also BH4 2HCL is FDA approved for use in phenylketonuria PKU along with dietary measures 18 However most people with PKU have little or no benefit from BH4 2HCL 19 Adverse effects EditThe 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 20 Interactions EditNo 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 20 Functions EditTetrahydrobiopterin 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 21 It works as a cofactor being required for an enzyme s activity as a catalyst mainly hydroxylases 7 Cofactor for tryptophan hydroxylases Edit 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 Edit Phenylalanine hydroxylase PAH catalyses the conversion of L phenylalanine PHE to L tyrosine TYR Therefore a deficiency in tetrahydrobiopterin can cause a toxic buildup of L phenylalanine which manifests as the severe neurological issues seen in phenylketonuria Cofactor for tyrosine hydroxylase Edit 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 22 currently this condition is typically treated with carbidopa levodopa which directly restores dopamine levels within the brain Cofactor for nitric oxide synthase Edit 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 23 Cofactor for ether lipid oxidase Edit Ether lipid oxidase alkylglycerol monooxygenase AGMO catalyses the conversion of 1 alkyl sn glycerol to 1 hydroxyalkyl sn glycerol History EditTetrahydrobiopterin was discovered to play a role as an enzymatic cofactor The first enzyme found to use tetrahydrobiopterin is phenylalanine hydroxylase PAH 24 Biosynthesis and recycling EditTetrahydrobiopterin 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 25 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 26 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 27 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 28 Research EditOther than PKU studies tetrahydrobiopterin has participated in clinical trials studying other approaches to solving conditions resultant from a deficiency of tetrahydrobiopterin These include autism depression 29 ADHD hypertension endothelial dysfunction and chronic kidney disease 30 31 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 32 Depression Edit In psychiatry tetrahydrobiopterin has been hypothesized to be involved in the pathophysiology of depression although evidence is inconclusive to date 33 Autism Edit 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 34 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 35 Cardiovascular disease Edit 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 36 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 37 atherosclerosis and hypoxic pulmonary hypertension 38 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 39 Neuroprotection in prenatal hypoxia Edit 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 40 Programmed cell death Edit GTPCH GCH1 and tetrahydrobiopterin were found to have a secondary role protecting against cell death by ferroptosis in cellular models by limiting the formation of toxic lipid peroxides 41 Tetrahydrobiopterin acts as a potent diffusable antioxidant that resists oxidative stress 42 and enables cancer cell survival via promotion of angiogenesis 43 References Edit Sapropterin Kuvan Use During Pregnancy Drugs com 17 May 2019 Retrieved 4 March 2020 a b Kuvan Product information Health Canada 25 April 2012 Retrieved 24 June 2022 a b c Kuvan sapropterin dihydrochloride tablet Kuvan sapropterin dihydrochloride powder for solution Kuvan sapropterin dihydrochloride powder for solution DailyMed 13 December 2019 Retrieved 4 March 2020 a b c d Kuvan EPAR European Medicines Agency EMA 4 March 2020 Retrieved 4 March 2020 Sapropterin Drugs com 28 February 2020 Retrieved 4 March 2020 International Non proprietary Names for Pharmaceutical Substances INN Fimea Retrieved 4 March 2020 a b Kappock TJ Caradonna JP November 1996 Pterin Dependent Amino Acid Hydroxylases Chemical Reviews 96 7 2659 2756 doi 10 1021 CR9402034 PMID 11848840 Cavaleri et al Blood concentrations of neopterin and biopterin in subjects with depression A systematic review and meta analysis Progress in Neuro Psychopharmacology and Biological Psychiatry 2023 120 110633 http dx doi org 10 1016 j pnpbp 2022 110633 Calka J 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 Bhagavan NV 2015 Essentials of Medical Biochemistry With Clinical Cases 2nd Edition USA Elsevier p 256 ISBN 978 0 12 416687 5 Schaub J Daumling S Curtius HC Niederwieser A Bartholome K Viscontini M et al August 1978 Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis Archives of Disease in Childhood 53 8 674 6 doi 10 1136 adc 53 8 674 PMC 1545051 PMID 708106 Drug Approval Package Kuvan Sapropterin Dihydrochloride NDA 022181 U S Food and Drug Administration FDA 24 March 2008 Retrieved 4 March 2020 Lay summary in Daniel A Shames 13 December 2007 Summary Review Application number 22 181 PDF U S Food and Drug Administration a b c d Kuvan sapropterin dihydrochloride Tablets and Powder for Oral Solution for PKU BioMarin Retrieved 4 March 2020 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 Herper M 28 July 2016 How Focusing On Obscure Diseases Made BioMarin A 15 Billion Company Forbes Retrieved 9 October 2017 BioMarin Announces Kuvan sapropterin dihydrochloride Patent Challenge Settlement BioMarin Pharmaceutical Inc 13 April 2017 Retrieved 9 October 2017 via PR Newswire Tetrahydrobiopterin Deficiency National Organization for Rare Disorders NORD Retrieved 9 October 2017 What are common treatments for phenylketonuria PKU NICHD 23 August 2013 Retrieved 12 September 2016 Camp KM Parisi MA Acosta PB Berry GT Bilder DA Blau N et al June 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 a b Haberfeld H ed 1 March 2017 Austria Codex in German Vienna Osterreichischer Apothekerverlag Kuvan 100 mg Tabletten Cavaleri et al Blood concentrations of neopterin and biopterin in subjects with depression A systematic review and meta analysis Progress in Neuro Psychopharmacology and Biological Psychiatry 2023 120 110633 http dx doi org 10 1016 j pnpbp 2022 110633 Genetics Home Reference GCH1 National Institutes of Health Wu G Meininger CJ 2009 Nitric oxide and vascular insulin resistance BioFactors 35 1 21 7 doi 10 1002 biof 3 PMID 19319842 S2CID 29828656 Kaufman S February 1958 A new cofactor required for the enzymatic conversion of phenylalanine to tyrosine PDF The Journal of Biological Chemistry 230 2 931 9 doi 10 1016 S0021 9258 18 70516 4 PMID 13525410 Thony B Auerbach G Blau N April 2000 Tetrahydrobiopterin biosynthesis regeneration and functions The Biochemical Journal 347 Pt 1 1 16 doi 10 1042 0264 6021 3470001 PMC 1220924 PMID 10727395 Kuzkaya N Weissmann N Harrison DG Dikalov S June 2003 Interactions of peroxynitrite tetrahydrobiopterin ascorbic acid and thiols implications for uncoupling endothelial nitric oxide synthase The Journal of Biological Chemistry 278 25 22546 54 doi 10 1074 jbc M302227200 PMID 12692136 Muller Delp JM November 2009 Ascorbic acid and tetrahydrobiopterin looking beyond nitric oxide bioavailability Cardiovascular Research 84 2 178 9 doi 10 1093 cvr cvp307 PMID 19744948 Gori T Burstein JM Ahmed S Miner SE Al Hesayen A Kelly S Parker JD September 2001 Folic acid prevents nitroglycerin induced nitric oxide synthase dysfunction and nitrate tolerance a human in vivo study Circulation 104 10 1119 23 doi 10 1161 hc3501 095358 PMID 11535566 Cavaleri et al Blood concentrations of neopterin and biopterin in subjects with depression A systematic review and meta analysis Progress in Neuro Psychopharmacology and Biological Psychiatry 2023 120 110633 http dx doi org 10 1016 j pnpbp 2022 110633 Search results for Kuvan ClinicalTrials gov U S National Library of Medicine BioMarin Initiates Phase 3b Study to Evaluate the Effects of Kuvan on Neurophychiatric Symptoms in Subjects with PKU BioMarin Pharmaceutical Inc 17 August 2010 Burton B Grant M Feigenbaum A Singh R Hendren R Siriwardena K et al March 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 3 415 24 doi 10 1016 j ymgme 2014 11 011 PMID 25533024 Cavaleri et al Blood concentrations of neopterin and biopterin in subjects with depression A systematic review and meta analysis Progress in Neuro Psychopharmacology and Biological Psychiatry 2023 120 110633 http dx doi org 10 1016 j pnpbp 2022 110633 Fernell E Watanabe Y Adolfsson I Tani Y Bergstrom M Hartvig P et al May 1997 Possible effects of tetrahydrobiopterin treatment in six children with autism clinical and positron emission tomography data a pilot study Developmental Medicine and Child Neurology 39 5 313 8 doi 10 1111 j 1469 8749 1997 tb07437 x PMID 9236697 S2CID 12761124 Frye RE Huffman LC Elliott GR July 2010 Tetrahydrobiopterin as a novel therapeutic intervention for autism Neurotherapeutics 7 3 241 9 doi 10 1016 j nurt 2010 05 004 PMC 2908599 PMID 20643376 Channon KM November 2004 Tetrahydrobiopterin regulator of endothelial nitric oxide synthase in vascular disease Trends in Cardiovascular Medicine 14 8 323 7 doi 10 1016 j tcm 2004 10 003 PMID 15596110 Alp NJ Mussa S Khoo J Cai S Guzik T Jefferson A et al September 2003 Tetrahydrobiopterin dependent preservation of nitric oxide mediated endothelial function in diabetes by targeted transgenic GTP cyclohydrolase I overexpression The Journal of Clinical Investigation 112 5 725 35 doi 10 1172 JCI17786 PMC 182196 PMID 12952921 Khoo JP Zhao L Alp NJ Bendall JK Nicoli T Rockett K et al April 2005 Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension Circulation 111 16 2126 33 doi 10 1161 01 CIR 0000162470 26840 89 PMID 15824200 Cunnington C Van Assche T Shirodaria C Kylintireas I Lindsay AC Lee JM et al March 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 Romanowicz J Leonetti C Dhari Z Korotcova L Ramachandra SD Saric N et al August 2019 Treatment With Tetrahydrobiopterin Improves White Matter Maturation in a Mouse Model for Prenatal Hypoxia in Congenital Heart Disease Journal of the American Heart Association 8 15 e012711 doi 10 1161 JAHA 119 012711 PMC 6761654 PMID 31331224 Kraft VA Bezjian CT Pfeiffer S Ringelstetter L Muller C Zandkarimi F et al January 2020 GTP Cyclohydrolase 1 Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling ACS Central Science 6 1 41 53 doi 10 1021 acscentsci 9b01063 PMC 6978838 PMID 31989025 Soula M Weber RA Zilka O Alwaseem H La K Yen F et al December 2020 Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers Nature Chemical Biology 16 12 1351 1360 doi 10 1038 s41589 020 0613 y PMC 8299533 PMID 32778843 Chen L Zeng X Wang J Briggs SS O Neill E Li J et al November 2010 Roles of tetrahydrobiopterin in promoting tumor angiogenesis The American Journal of Pathology 177 5 2671 2680 doi 10 2353 ajpath 2010 100025 PMC 2966821 PMID 20847284 Further reading Edit Clinical Review Report Sapropterin dihydrochloride Kuvan CADTH Common Drug Reviews Ottawa Canada Canadian Agency for Drugs and Technologies in Health CADTH September 2017 PMID 30462435 Bookshelf ID NBK533813 Blau N June 2016 Genetics of Phenylketonuria Then and Now Human Mutation 37 6 508 15 doi 10 1002 humu 22980 PMID 26919687 Dubois EA Cohen AF June 2010 Sapropterin British Journal of Clinical Pharmacology 69 6 576 7 doi 10 1111 j 1365 2125 2010 03643 x PMC 2883749 PMID 20565448 Muntau AC Adams DJ Belanger Quintana A Bushueva TV Cerone R Chien YH et al May 2019 International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria Molecular Genetics and Metabolism 127 1 1 11 doi 10 1016 j ymgme 2019 04 004 PMID 31103398 Qu J Yang T Wang E Li M Chen C Ma L et al May 2019 Efficacy and safety of sapropterin dihydrochloride in patients with phenylketonuria A meta analysis of randomized controlled trials British Journal of Clinical Pharmacology 85 5 893 899 doi 10 1111 bcp 13886 PMC 6475685 PMID 30720885 van Wegberg AM MacDonald A Ahring K Belanger Quintana A Blau N Bosch AM et al October 2017 The complete European guidelines on phenylketonuria diagnosis and treatment Orphanet Journal of Rare Diseases 12 1 162 doi 10 1186 s13023 017 0685 2 PMC 5639803 PMID 29025426 External links Edit Sapropterin Drug Information Portal U S National Library of Medicine Sapropterin dihydrochloride Drug Information Portal U S National Library of Medicine Portal Medicine Retrieved from https en wikipedia org w index php title Tetrahydrobiopterin amp oldid 1148851102, wikipedia, wiki, book, books, library,

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