Tetrahydrobiopterin

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| _other_data=(6R)-2-Amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydropteridin-4(1H)-one

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Tetrahydrobiopterin (BH₄, THB), also known as sapropterin (INN),<ref>Template:Cite web</ref><ref>Template:Cite web</ref> is a cofactor of the three aromatic amino acid hydroxylase enzymes,<ref name=Cara>Template:Cite journal</ref> 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.<ref> 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 </ref><ref>Template:Cite journal</ref> Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin).<ref>Template:Cite book</ref>Template:Citation needed

Tetrahydrobiopterin is available as a tablet for oral administration in the form of sapropterin dihydrochloride (BH4*2HCL).<ref>Template:Cite journal</ref><ref name="Kuvan FDA label">Template:Cite web</ref><ref name="Kuvan EPAR">Template:Cite web</ref> It was approved for use in the United States as a tablet in December 2007<ref>Template:Cite web

• Template:Lay source</ref><ref name="BioMarin Kuvan">Template:Cite web</ref> and as a powder in December 2013.<ref>Template:Cite web</ref><ref name="BioMarin Kuvan" /> It was approved for use in the European Union in December 2008,<ref name="Kuvan EPAR" /> Canada in April 2010,<ref name="Kuvan CA Product information">Template:Cite web</ref> and Japan in July 2008.<ref name="BioMarin Kuvan" /> It is sold under the brand names Kuvan and Biopten.<ref name="Kuvan EPAR" /><ref name="Kuvan FDA label" /><ref name="BioMarin Kuvan" /> The typical cost of treating a patient with Kuvan is Template:US$ per year.<ref>Template:Cite web</ref> BioMarin holds the patent for Kuvan until at least 2024, but Par Pharmaceutical has a right to produce a generic version by 2020.<ref>Template:Cite web</ref>

Medical uses

Sapropterin is indicated in tetrahydrobiopterin deficiency caused by GTP cyclohydrolase I (GTPCH) deficiency, or 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency.<ref>Template:Cite web</ref> Also, BH4*2HCL is FDA approved for use in phenylketonuria (PKU), along with dietary measures.<ref name=NIH2013Tx>Template:Cite web</ref> However, most people with PKU have little or no benefit from BH4*2HCL.<ref>Template:Cite journal</ref>

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.<ref name="AustriaCodex">Template:Cite book</ref>

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.<ref name="AustriaCodex" />

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.<ref> 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 </ref> It works as a cofactor, being required for an enzyme's activity as a catalyst, mainly hydroxylases.<ref name=Cara/>

Cofactor for tryptophan hydroxylases

Template:Further 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;<ref>Template:Cite web</ref> 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.<ref>Template:Cite journal</ref> 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.<ref name="pmid29596860">Template:Cite journal</ref>

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).<ref>Template:Cite journal</ref>

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).<ref name="pmid10727395">Template:Cite journal</ref>

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,<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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,<ref> 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 </ref> ADHD, hypertension, endothelial dysfunction, and chronic kidney disease.<ref>Template:Cite web</ref><ref>Template:Cite news</ref> 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.<ref>Template:Cite journal</ref>

Depression

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

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.<ref>Template:Cite journal</ref> 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."<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> 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,<ref>Template:Cite journal</ref> atherosclerosis, and hypoxic pulmonary hypertension.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> Tetrahydrobiopterin acts as a potent, diffusable antioxidant that resists oxidative stress<ref>Template:Cite journal</ref> and enables cancer cell survival via promotion of angiogenesis.<ref>Template:Cite journal</ref>

Further reading

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External links

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