Tetrahydrobiopterin

"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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.164.121 Edit this at Wikidata
Chemical and physical data
FormulaC9H15N5O3
Molar mass241.251 g·mol−1
3D model (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),[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 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]

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

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 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;[22] 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.[23] 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.[24]

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).[25]

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).[26]

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,[27] 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.[28] 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.[29]

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,[30] ADHD, hypertension, endothelial dysfunction, and chronic kidney disease.[31][32] 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.[33]

Depression

In psychiatry, tetrahydrobiopterin has been hypothesized to be involved in the pathophysiology of depression, although evidence is inconclusive to date.[34]

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.[35] 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."[36]

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.[37] 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,[38] atherosclerosis, and hypoxic pulmonary hypertension.[39] 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.[40]

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.[41]

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.[42] Tetrahydrobiopterin acts as a potent, diffusable antioxidant that resists oxidative stress[43] and enables cancer cell survival via promotion of angiogenesis.[44]

References

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  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.
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Tabletop fantasy role-playing game Amber Diceless Roleplaying GameCover of the main Amber DRPG rulebook (art by Stephen Hickman)DesignersErick WujcikPublishersPhage PressGuardians of OrderPublication1991GenresFantasySystemsCustom (direct comparison of statistics without dice) The Amber Diceless Roleplaying Game is a role-playing game created and written by Erick Wujcik, set in the fictional universe created by author Roger Zelazny for his Chronicles of Amber. The game is unusual in that no di...

 

Пхурба

У этого термина существуют и другие значения, см. Кила. Пхурба из фильма Тень Кила (санскр.. कील IAST: kila; тиб. ཕུར་བ, Вайли phur ba; кол или гвоздь) — ритуальный кинжал или кол, обычно имеющий форму рукоятки в виде трёх голов гневного божества и трёхгранную форму клина, вероят...

Niimi Domain

Administrative division in western Japan during the Edo period (1600-1871) Niimi Domain新見藩Domain of Japan1697–1871 Mon of the Seki clan CapitalNiimi Jin'yaArea • Coordinates34°59′11.18″N 133°28′12.84″E / 34.9864389°N 133.4702333°E / 34.9864389; 133.4702333 HistoryHistorical eraEdo period• Established 1697• Abolition of the han system 1871 Contained within • ProvinceBitchū Province Today part ofOkayama Pref...

 

Harlequin duck

Species of bird This article is about the species of wild sea duck. For the domestic duck breed, see Welsh harlequin. This article includes a list of general references, but it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (February 2010) (Learn how and when to remove this template message) Harlequin duck Adult drake Conservation status Least Concern (IUCN 3.1)[1] Scientific classification Domain: Eukar...

 

Armando Iannucci

Scottish comedian, film director and producer Armando IannucciOBEIannucci in 2017BornArmando Giovanni Iannucci (1963-11-28) 28 November 1963 (age 60)Glasgow, ScotlandAlma materUniversity of GlasgowUniversity College, OxfordSpouse Rachel Jones ​(m. 1990)​Children3Comedy careerMediumTelevision, film, radio, stand up comedyYears active1990–presentGenresSitcom, political satire Armando Giovanni Iannucci OBE (/jəˈnuːtʃi/; born 28 November 1963) is a Sco...

The Ugly Beats

American garage rock band The Ugly BeatsBackground informationOriginAustin, TexasGenresGarage rock, popYears active2003–presentLabelsGet Hip RecordsMembersBobby TrimbleDaniel WilcoxJason GentryJeanine AttawayJoe EmeryPast membersJake GarciaSteve AustinWebsitehttp://www.theuglybeats.com/ The Ugly Beats is a garage rock band from Austin, Texas.[1][2] Born in 2003 from the remnants of Austin's Sir Finks,[3] their first album Bring On The Beats! appeared in 2004, with a ...

 

Zakaria Zouggary

Dutch-Moroccan kickboxer Zakaria ZouggaryBorn (1995-06-22) June 22, 1995 (age 28)Rotterdam, NetherlandsNationalityDutchMoroccanHeight170 cm (5 ft 7 in)[1]Weight65 kg (143 lb; 10 st 3 lb)DivisionFeatherweightStyleKickboxingStanceOrthodoxFighting out ofMoroccoTeamMelvin Fighting FactoryOude Westen Gym[2]TrainerKhalid ChennoufYears active2013-presentKickboxing recordTotal40Wins33By knockout16Losses6By knockout3Draws1 Zakaria Zougg...

 

Strategi Solo vs Squad di Free Fire: Cara Menang Mudah!