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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 metabolism 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][6] Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin).[7]

Tetrahydrobiopterin is available as a tablet for oral administration in the form of sapropterin dihydrochloride (BH4*2HCL).[8][9][10] It was approved for use in the United States as a tablet in December 2007[11][12] and as a powder in December 2013.[13][12] It was approved for use in the European Union in December 2008,[10] Canada in April 2010,[14] and Japan in July 2008.[12] It is sold under the brand names Kuvan and Biopten.[10][9][12] 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]

Medical uses

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

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

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

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.[5] It works as a cofactor, being required for an enzyme's activity as a catalyst, mainly hydroxylases.[4]

Cofactor for tryptophan hydroxylases

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 a toxic buildup of L-phenylalanine, which manifests as the severe neurological issues seen in phenylketonuria.

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;[21] 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.[22] As a co-factor for nitric oxide synthase, tetrahydrobiopterin supplementation has shown beneficial results for the treatment of endothelial dysfunction in animal experiments and clinical trials, although the tendency of BH4 to become oxidized to BH2 remains a problem.[23]

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).[24]

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).[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

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

Depression

In psychiatry, tetrahydrobiopterin has been hypothesized to be involved in the pathophysiology of depression, although evidence is inconclusive to date.[5]

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.[32] 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."[33]

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.[34] 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,[35] atherosclerosis, and hypoxic pulmonary hypertension.[36] 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.[37]

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.[38]

Programmed cell death

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.[39] Tetrahydrobiopterin acts as a potent, diffusable antioxidant that resists oxidative stress[40] and enables cancer cell survival via promotion of angiogenesis.[41]

Further reading

External links

References

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  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. Pterin-Dependent Amino Acid Hydroxylases Chemical Reviews, November 1996^
  5. 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^
  6. 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, 2006^
  7. Essentials of Medical Biochemistry With Clinical Cases, 2nd Edition Elsevier, 2015^
  8. Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis Archives of Disease in Childhood, August 1978^
  9. Kuvan- sapropterin dihydrochloride tablet Kuvan- sapropterin dihydrochloride powder, for solution Kuvan- sapropterin dihydrochloride powder, for solution DailyMed, 13 December 2019, retrieved 4 March 2020^
  10. Kuvan EPAR European Medicines Agency (EMA), 4 March 2020, retrieved 4 March 2020^
  11. Drug Approval Package: Kuvan (Sapropterin Dihydrochloride) NDA #022181 U.S. Food and Drug Administration (FDA), 24 March 2008, retrieved 4 March 2020^
  12. Kuvan (sapropterin dihydrochloride) Tablets and Powder for Oral Solution for PKU BioMarin, retrieved 4 March 2020^
  13. 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^
  14. Kuvan Product information Health Canada, 25 April 2012, retrieved 24 June 2022^
  15. How Focusing On Obscure Diseases Made BioMarin A $15 Billion Company Forbes, 28 July 2016, retrieved 2017-10-09^
  16. BioMarin Announces Kuvan (sapropterin dihydrochloride) Patent Challenge Settlement BioMarin Pharmaceutical Inc., 2017-04-13, retrieved 2017-10-09^
  17. Tetrahydrobiopterin Deficiency National Organization for Rare Disorders (NORD), retrieved 2017-10-09^
  18. What are common treatments for phenylketonuria (PKU)? NICHD, 2013-08-23, retrieved 12 September 2016^
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  20. Austria-Codex Österreichischer Apothekerverlag, 1 March 2017^
  21. Genetics Home Reference: GCH1 National Institutes of Health^
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  24. A new cofactor required for the enzymatic conversion of phenylalanine to tyrosine The Journal of Biological Chemistry, February 1958^
  25. Tetrahydrobiopterin biosynthesis, regeneration and functions The Biochemical Journal, April 2000^
  26. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase The Journal of Biological Chemistry, June 2003^
  27. Ascorbic acid and tetrahydrobiopterin: looking beyond nitric oxide bioavailability Cardiovascular Research, November 2009^
  28. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study Circulation, September 2001^
  29. Search results for Kuvan ClinicalTrials.gov, U.S. National Library of Medicine^
  30. BioMarin Initiates Phase 3b Study to Evaluate the Effects of Kuvan on Neurophychiatric Symptoms in Subjects with PKU BioMarin Pharmaceutical Inc, 17 August 2010^
  31. 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, March 2015^
  32. Possible effects of tetrahydrobiopterin treatment in six children with autism--clinical and positron emission tomography data: a pilot study Developmental Medicine and Child Neurology, May 1997^
  33. Tetrahydrobiopterin as a novel therapeutic intervention for autism Neurotherapeutics, July 2010^
  34. Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease Trends in Cardiovascular Medicine, November 2004^
  35. Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression The Journal of Clinical Investigation, September 2003^
  36. Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension Circulation, April 2005^
  37. Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease Circulation, March 2012^
  38. Treatment With Tetrahydrobiopterin Improves White Matter Maturation in a Mouse Model for Prenatal Hypoxia in Congenital Heart Disease Journal of the American Heart Association, August 2019^
  39. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling ACS Central Science, January 2020^
  40. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers Nature Chemical Biology, December 2020^
  41. Roles of tetrahydrobiopterin in promoting tumor angiogenesis The American Journal of Pathology, November 2010^