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Tetrahydrobiopterin
INN: Sapropterin

Clinical data
Trade names	Kuvan, Biopten
Other names	Sapropterin hydrochloride (JAN JP), Sapropterin dihydrochloride (USAN US)
AHFS/Drugs.com	Monograph
MedlinePlus	a608020
License data	EU EMA: by INN US DailyMed: Sapropterin US FDA: Sapropterin
Pregnancy category	AU: B1
Routes of administration	By mouth
ATC code	A16AX07 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only US: ℞-only EU: Rx-only In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life	4 hours (healthy adults) 6–7 hours (PKU patients)
Identifiers
IUPAC name (6R)-2-Amino-6--5,6,7,8-tetrahydropteridin-4(1H)-one
CAS Number	62989-33-7 as salt: 69056-38-8
PubChem CID	135398654
IUPHAR/BPS	5276
DrugBank	DB00360 as salt: DBSALT001133
ChemSpider	40270 as salt: 552166
UNII	EGX657432I
KEGG	D08505 as salt: D01798
ChEBI	CHEBI:59560 as salt: CHEBI:32120
ChEMBL	ChEMBL1201774 as salt: ChEMBL1201775
PDB ligand	H4B (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID1041138
ECHA InfoCard	100.164.121
Chemical and physical data
Formula	C9H15N5O3
Molar mass	241.251 g·mol
3D model (JSmol)	Interactive image
SMILES CC(C(C1CNC2=C(N1)C(=O)N=C(N2)N)O)O
InChI 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 Key:FNKQXYHWGSIFBK-RPDRRWSUSA-N
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Tetrahydrobiopterin (BH₄, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, 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. Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin).

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

Medical uses

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

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.

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.

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.

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; 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. 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.

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).

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).

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, 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. 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.

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, ADHD, hypertension, endothelial dysfunction, and chronic kidney disease. 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.

Depression

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

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. 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."

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. 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, atherosclerosis, and hypoxic pulmonary hypertension. 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.

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.

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

References

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Further reading

• "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. hdl:11336/126862. 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

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

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• Pteridines
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