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| Targets |
Tetrahydrobiopterin acts as an essential cofactor for multiple enzymes: phenylalanine-4-hydroxylase (converts phenylalanine to tyrosine), tyrosine hydroxylase (converts tyrosine to L-dopa), and tryptophan hydroxylase (converts tryptophan to 5-hydroxytryptophan). These enzymes are essential for the biosynthesis of the neurotransmitters dopamine, noradrenaline, and adrenaline. BH4 is also an essential cofactor for all three nitric oxide synthase (NOS) isoforms, which produce nitric oxide from L-arginine.
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| ln Vitro |
Microastrocyte cultures in hyperoxic environments, either with or without 100 μM tetrahydrobiopterin supplementation. Tetrahydrobiopterin supplementation significantly prevented hyperoxic induction by reducing Iba-1 and TSP-1 expression compared with normoxia (21% O2) Activation of astrocytes and prevention of microvascular damage in choroidal explants. Astrocytes were exposed to hyperoxic-induced oxidative media for 24 hours. 1].
Tetrahydrobiopterin functions as a cofactor rather than a direct inhibitor or activator of enzyme activity. In vitro, BH4 is required for the catalytic activity of phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase, and all three NOS isoforms. It participates in electron transfer during the hydroxylation reactions. BH4 deficiency in vitro leads to reduced enzyme activity and impaired neurotransmitter synthesis. The compound is also involved in the promotion of neurotransmitter release in the brain and the regulation of human melanogenesis. |
| ln Vivo |
Three to five EB pools were taken from WT and hph-1 mice at postnatal ages 7, 14, and 22 and analyzed by LC-MS/MS in order to determine the amounts of tetrahydrobiopterin in EBs. ..According to LC-MS/MS analysis, the concentration levels of tetrahydrobiopterin in hph-1-driven tissues were significantly lower by around 90%, P7, P14, and P22, respectively, when compared to WT groups [1].
In vivo, tetrahydrobiopterin is essential for maintaining normal neurotransmitter levels and nitric oxide production. Defects in BH4 production or in the enzyme dihydropteridine reductase (DHPR) cause phenylketonuria type IV and dopa-responsive dystonias. BH4 has been implicated in Parkinson's disease, Alzheimer's disease, and depression. As an essential cofactor, BH4 supplementation can restore enzyme activity in conditions of BH4 deficiency. The compound is also used in the treatment of tetrahydrobiopterin deficiency and related metabolic disorders. |
| Enzyme Assay |
In vitro enzyme activity assays for tetrahydrobiopterin typically measure the hydroxylation activity of phenylalanine hydroxylase, tyrosine hydroxylase, or tryptophan hydroxylase in the presence of BH4. Enzyme preparations are incubated with substrate (phenylalanine, tyrosine, or tryptophan) and varying concentrations of BH4 (typically 0-100 μM) in appropriate buffer systems. The reaction is initiated by addition of the enzyme and terminated by acidification. Product formation (tyrosine, L-dopa, or 5-hydroxytryptophan) is quantified by HPLC with fluorescence or electrochemical detection. For NOS assays, the conversion of [³H]arginine to [³H]citrulline is measured in the presence of BH4, NADPH, and calcium/calmodulin.
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| Cell Assay |
In vitro cell-based assays for BH4 typically involve culturing cells (e.g., neuronal cell lines, endothelial cells) in BH4-deficient or BH4-supplemented media. Cells are treated with varying concentrations of BH4 (typically 1-100 μM) for 24-72 hours. Neurotransmitter production (dopamine, norepinephrine, serotonin) is measured in cell lysates or culture media by HPLC. Nitric oxide production is assessed by measuring nitrite/nitrate levels using the Griess assay. Cell viability and proliferation are monitored using MTT or similar assays. Gene expression of tyrosine hydroxylase, tryptophan hydroxylase, and NOS isoforms can be measured by qRT-PCR or Western blot.
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| Animal Protocol |
In vivo animal studies for BH4 typically use rodent models of BH4 deficiency or neurological disorders. BH4 is administered orally or intraperitoneally at doses ranging from 1-50 mg/kg. In phenylketonuria models, blood phenylalanine levels are measured before and after BH4 administration to assess efficacy. In Parkinson's disease models, behavioral tests (e.g., rotarod, open field) are conducted, and brain neurotransmitter levels are measured post-mortem by HPLC. For NOS-related studies, blood pressure and endothelial function are assessed. Standard protocols involve daily administration for 1-4 weeks, with endpoint measurements including tissue BH4 levels, enzyme activity, and neurotransmitter concentrations.
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| ADME/Pharmacokinetics |
Tetrahydrobiopterin is administered orally or intraperitoneally. It is soluble in water and common organic solvents. The compound has a short half-life and is subject to oxidation to dihydrobiopterin (BH2) and biopterin. BH4 is regenerated from BH2 via the NADPH-dependent enzyme dihydropteridine reductase (DHPR). The compound is present in all tissues and crosses the blood-brain barrier to some extent. Detailed pharmacokinetic parameters (Cmax, Tmax, AUC, half-life) are dose-dependent and vary by route of administration. Bioavailability is influenced by the compound's instability and rapid oxidation.
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| Toxicity/Toxicokinetics |
Tetrahydrobiopterin is generally well-tolerated as an endogenous compound. However, high doses may cause gastrointestinal disturbances, headache, and hypersensitivity reactions. As a cofactor for neurotransmitter synthesis, excess BH4 could theoretically alter neurotransmitter levels, but toxicity is minimal at physiological doses. In BH4 deficiency disorders, supplementation is safe and effective. The compound has been used clinically for the treatment of tetrahydrobiopterin deficiency and phenylketonuria. No significant genotoxicity or carcinogenicity has been reported for BH4.
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| References | |
| Additional Infomation |
5,6,7,8-Tetrahydrobiopterin is a tetrahydropterin, belonging to the biopterin family, and is also a diol. It functions as a cofactor, coenzyme, nutritional supplement, and human metabolite. Tetrahydrobiopterin is an essential cofactor for the activity of aromatic amino acid hydroxylases. Tetrahydrobiopterin can degrade phenylalanine and promote the biosynthesis of various neurotransmitters and the production of nitric oxide.
Tetrahydrobiopterin (BH4) is a naturally occurring cofactor essential for neurotransmitter synthesis and nitric oxide production. It is classified as an antioxidant and protective agent (ATC code A16AX). BH4 is also known as sapropterin and is used clinically as a therapeutic agent for tetrahydrobiopterin deficiency and certain forms of phenylketonuria. The compound is involved in the pathogenesis of several neurological disorders, including Parkinson's disease, Alzheimer's disease, and depression, making it a target for therapeutic intervention. BH4 supplementation is approved for the treatment of hyperphenylalaninemia due to BH4 deficiency. Ongoing research is exploring its potential in cardiovascular diseases, endothelial dysfunction, and neuropsychiatric disorders. |
| Molecular Formula |
C9H15N5O3
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|---|---|
| Molecular Weight |
241.25
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| Exact Mass |
241.117
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| CAS # |
17528-72-2
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| Related CAS # |
Sapropterin dihydrochloride;69056-38-8;Sapropterin;62989-33-7
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| PubChem CID |
135402045
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| Appearance |
White to off-white solid powder
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| Density |
1.89g/cm3
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| Boiling Point |
506.6ºC at 760mmHg
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| Flash Point |
260.2ºC
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| LogP |
0.761
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
17
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| Complexity |
405
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
FNKQXYHWGSIFBK-UHFFFAOYSA-N
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| InChi Code |
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)
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| Chemical Name |
2-amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-3H-pteridin-4-one
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| Synonyms |
Tetrahydrobiopterin
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~207.25 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (10.36 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (10.36 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (10.36 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.1451 mL | 20.7254 mL | 41.4508 mL | |
| 5 mM | 0.8290 mL | 4.1451 mL | 8.2902 mL | |
| 10 mM | 0.4145 mL | 2.0725 mL | 4.1451 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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