Tetrahydrobiopterin

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"BH4" redirects here. For the anion, see Borohydride. For the edition of the Hebrew Bible, see Biblia Hebraica Stuttgartensia.
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
JSmol)
  • 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 checkY
  • Key:FNKQXYHWGSIFBK-RPDRRWSUSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN),

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
]

Medical use

Tetrahydrobiopterin is available as a tablet for

Par Pharmaceutical has a right to produce a generic version by 2020.[16]

Sapropterin is indicated in

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

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

hydroxylases.[7]

Cofactor for tryptophan hydroxylases

Further information: Tryptophan hydroxylase

Tetrahydrobiopterin is a cofactor for

5-hydroxytryptophan
(5-HTP).

Cofactor for phenylalanine hydroxylase

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

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

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

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

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

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

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

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

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.[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

Since

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

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

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

  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. ^
    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. PMID 16584085
    .
  10. ISBN 978-0-12-416687-5
    .
  11. 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.
  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. 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. S2CID 29828656
    .
  24. PMID 13525410
    .
  25. PMID 10727395
    .
  26. PMID 12692136
    .
  27. PMID 19744948
    .
  28. 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. 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. S2CID 12761124
    .
  35. PMID 20643376
    .
  36. PMID 15596110
    .
  37. PMID 12952921
    .
  38. PMID 15824200
    .
  39. PMID 22315282
    .
  40. PMID 31331224
    .
  41. PMID 31989025
    .
  42. PMID 32778843
    .
  43. PMID 20847284
    .

Further reading

External links
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