Tetrahydrobiopterin
Tetrahydrobiopterin, also known as sapropterin, is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the metabolism of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin, melatonin, dopamine, norepinephrine, epinephrine, and is a cofactor for the production of nitric oxide by the nitric oxide synthases. Chemically, its structure is that of a reduced pteridine derivative.
Tetrahydrobiopterin is available as a tablet for oral administration in the form of sapropterin dihydrochloride. 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 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 deficiency, or 6-pyruvoyltetrahydropterin synthase deficiency. Also, BH4*2HCL is FDA approved for use in phenylketonuria, 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 for the conversion of L-tryptophan to 5-hydroxytryptophan.Cofactor for phenylalanine hydroxylase
Phenylalanine hydroxylase catalyses the conversion of L-phenylalanine to L-tyrosine. 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 catalyses the conversion of L-tyrosine to L-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 catalyses the conversion of a guanidino nitrogen of L-arginine to nitric oxide. 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 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.Biosynthesis and recycling
Tetrahydrobiopterin is biosynthesized from guanosine triphosphate by three chemical reactions mediated by the enzymes GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase, and sepiapterin reductase.BH4 can be oxidized by one or two electron reactions, to generate BH4 or BH3 radical and BH2, respectively. Research shows that ascorbic acid can reduce BH3 radical into BH4, preventing the BH3 radical from reacting with other free radicals. Without this recycling process, uncoupling of the endothelial nitric oxide synthase 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.