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Identification
Name Tetrahydrobiopterin
Accession Number DB00360 (APRD01297)
Type small molecule
Groups approved
Description

Tetrahydrobiopterin or BH4 is a cofactor in the synthesis of nitric oxide. It is also essential in the conversion of phenylalanine to tyrosine by the enzyme phenylalanine-4-hydroxylase; the conversion of tyrosine to L-dopa by the enzyme tyrosine hydroxylase; and conversion of tryptophan to 5-hydroxytryptophan via tryptophan hydroxylase. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
5,6,7,8 Tetrahydrobiopterin
BH4
sapropterin
Salts Not Available
Brand names
Name Company
Dapropterin
Kuvan
Phenoptin
Sapropterin
Brand mixtures Not Available
Categories
  • Dietary supplement
  • Cofactor
CAS number 17528-72-2
Weight Average: 241.2471
Monoisotopic: 241.117489371
Chemical Formula C9H15N5O3
InChI Key InChIKey=FNKQXYHWGSIFBK-UHFFFAOYSA-N
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)
Plain Text
IUPAC Name
2-amino-6-(1,2-dihydroxypropyl)-1,4,5,6,7,8-hexahydropteridin-4-one
SMILES
CC(O)C(O)C1CNC2=C(N1)C(=O)N=C(N)N2
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes
  • Pterins
Substructures
  • Pterins
  • Hydroxy Compounds
  • Aliphatic and Aryl Amines
  • Pyrimidines and Derivatives
  • Amino Alcohols
  • Alcohols and Polyols
  • Heterocyclic compounds
  • Aromatic compounds
  • Cyanamides
Pharmacology
Indication For the treatment of tetrahydrobiopterin (BH4) deficiency.
Pharmacodynamics Tetrahydrobiopterin (BH4) is used to convert several amino acids, including phenylalanine, to other essential molecules in the body including neurotransmitters. Tetrahydrobiopterin deficiency can be caused by mutations in GTP cyclohydrolase 1 (GCH1), 6-pyruvoyl-tetrahydropterin synthase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (PCBD1), 6-pyruvoyltetrahydropterin synthase (PTS), and quinoid dihydropteridine reductase (QDPR) genes. These genes make the enzymes that are critical for producing and recycling tetrahydrobiopterin. If one of the enzymes fails to function correctly because of a gene mutation, little or no tetrahydrobiopterin is produced. As a result, phenylalanine from the diet builds up in the bloodstream and other tissues and can damage nerve cells in the brain. High levels of phenylalanine can result in signs and symptoms ranging from temporary low muscle tone to mental retardation, movement disorders, difficulty swallowing, seizures, behavioral problems, progressive problems with development, and an inability to control body temperature.
Mechanism of action Tetrahydrobiopterin (BH4) is a natural co-factor or co-enzyme for phenylalanine-4-hydroxylase (PAH),Tetrahydrobiopterine, and tryptophan-5-hydroxylase. Tetrahydrobiopterin is also a natural co-factor for nitrate oxide synthase. Therefore BH4 is required for the conversion of phenylalanine to tyrosine, for the production of epinephrine (adrenaline) and the synthesis of the monoamine neuro-transmitters, serotonin, dopamine, and norepinephrine (noradrenaline). It is also involved in apoptosis and other cellular events mediated by nitric oxide production. As a coenzyme, BH4 reacts with molecular oxygen to form an active oxygen intermediate that can hydroxylate substrates. In the hydroxylation process, the co-enzyme loses two electrons and is regenerated in vivo in an NADH-dependent reaction. As a co-factor for PAH, tetrahydrobiopterin allows the conversion of phenylalanine to tyrosine and reduces the level of phenylalanine in the bloodstream, thereby reducing the toxic effects of of this amino acid. Normal serum concentrations of phenylalanine are 100 micomolar, while elevated (toxic) levels are typically >1200 micromolar. Individuals with a deficiency in tetrahydrobiopterin are not able to efficiently convert phenylalanine to tyrosine. The excess levels provided by tetrahydrobiopterin supplementation help improve enzyme efficiency. As a co-factor for tyrosine hydroxylase, BH4 facilitates the conversion of tyrosine to L-dopa while as a co-factor for tryptophan hydroxylase, BH4 allows the conversion of tryptophan to 5-hydroxytryptophan, which is then converted to serotonin.
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism Not Available
Route of elimination Not Available
Half life Not Available
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Biomarin pharmaceutical inc
Packagers
Dosage forms Not Available
Prices
Unit description Cost Unit
Kuvan 100 mg tablet 36.5 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 7566462 2005-11-16 2025-11-16
United States 7566714 2004-11-17 2024-11-17
Canada 2545968 2010-03-09 2024-11-17
Properties
State solid
Experimental Properties
Property Value Source
melting point 250-255 °C (hydrochloride salt) Not Available
water solubility >20 mg/mL (dichloride salt) Not Available
logP -1.7 Not Available
Predicted Properties
Property Value Source
water solubility 2.21e+00 g/l ALOGPS
logP -1.7 ALOGPS
logP -2.7 ChemAxon
logS -2 ALOGPS
pKa (strongest acidic) 10.01 ChemAxon
pKa (strongest basic) 3.58 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 8 ChemAxon
hydrogen donor count 6 ChemAxon
polar surface area 132 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 68.43 ChemAxon
polarizability 23.4 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Thony B, Auerbach G, Blau N: Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J. 2000 Apr 1;347 Pt 1:1-16. Pubmed
External Links
Resource Link
KEGG Compound C00272 Link_out
PubChem Compound 1125 Link_out
PubChem Substance 46508597 Link_out
ChemSpider 1093 Link_out
ChEBI 15372 Link_out
ChEMBL 15372 Link_out
Therapeutic Targets Database DNC000425 Link_out
PharmGKB PA161990676 Link_out
HET THB Link_out
Wikipedia http://en.wikipedia.org/wiki/Tetrahydrobiopterin Link_out
ATC Codes
  • A16AX07
AHFS Codes Not Available
PDB Entries
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Nitric-oxide synthase, endothelial

Pharmacological action: yes
Actions: cofactor

Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. No mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets

Organism class: human
UniProt ID: P29474 Link_out
Gene: NOS3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Heller R, Munscher-Paulig F, Grabner R, Till U: L-Ascorbic acid potentiates nitric oxide synthesis in endothelial cells. J Biol Chem. 1999 Mar 19;274(12):8254-60. Pubmed
  2. Huang A, Vita JA, Venema RC, Keaney JF Jr: Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem. 2000 Jun 9;275(23):17399-406. Pubmed
  3. Berka V, Tsai AL: Characterization of interactions among the heme center, tetrahydrobiopterin, and L-arginine binding sites of ferric eNOS using imidazole, cyanide, and nitric oxide as probes. Biochemistry. 2000 Aug 8;39(31):9373-83. Pubmed
  4. Gorren AC, Bec N, Schrammel A, Werner ER, Lange R, Mayer B: Low-temperature optical absorption spectra suggest a redox role for tetrahydrobiopterin in both steps of nitric oxide synthase catalysis. Biochemistry. 2000 Sep 26;39(38):11763-70. Pubmed
  5. Shinozaki K, Nishio Y, Okamura T, Yoshida Y, Maegawa H, Kojima H, Masada M, Toda N, Kikkawa R, Kashiwagi A: Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats. Circ Res. 2000 Sep 29;87(7):566-73. Pubmed
  6. Gorren AC, Mayer B: Tetrahydrobiopterin in nitric oxide synthesis: a novel biological role for pteridines. Curr Drug Metab. 2002 Apr;3(2):133-57. Pubmed

2. Phenylalanine-4-hydroxylase

Pharmacological action: yes
Actions: cofactor
Organism class: human
UniProt ID: P00439 Link_out
Gene: PAH Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zekanowski C, Nowacka M, Sendecka E, Sowik M, Cabalska B, Bal J: Identification of Mutations Causing 6-Pyruvoyl- Tetrahydrobiopterin Synthase Deficiency in Polish Patients With Variant Hyperphenylalaninemia. Mol Diagn. 1998 Dec;3(4):237-239. Pubmed
  2. Werner ER, Habisch HJ, Gorren AC, Schmidt K, Canevari L, Werner-Felmayer G, Mayer B: Contrasting effects of N5-substituted tetrahydrobiopterin derivatives on phenylalanine hydroxylase, dihydropteridine reductase and nitric oxide synthase. Biochem J. 2000 Jun 15;348 Pt 3:579-83. Pubmed
  3. Fitzpatrick PF: Tetrahydropterin-dependent amino acid hydroxylases. Annu Rev Biochem. 1999;68:355-81. Pubmed
  4. Ayling JE, Bailey SW, Boerth SR, Giugliani R, Braegger CP, Thony B, Blau N: Hyperphenylalaninemia and 7-pterin excretion associated with mutations in 4a-hydroxy-tetrahydrobiopterin dehydratase/DCoH: analysis of enzyme activity in intestinal biopsies. Mol Genet Metab. 2000 Jul;70(3):179-88. Pubmed
  5. Jennings IG, Teh T, Kobe B: Essential role of the N-terminal autoregulatory sequence in the regulation of phenylalanine hydroxylase. FEBS Lett. 2001 Jan 19;488(3):196-200. Pubmed

3. Tyrosine 3-monooxygenase

Pharmacological action: yes
Actions: cofactor

Plays an important role in the physiology of adrenergic neurons

Organism class: human
UniProt ID: P07101 Link_out
Gene: TH Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Koshimura K, Tanaka J, Murakami Y, Kato Y: Enhancement of neuronal survival by 6R-tetrahydrobiopterin. Neuroscience. 1999 Jan;88(2):561-9. Pubmed
  2. Flatmark T, Almas B, Knappskog PM, Berge SV, Svebak RM, Chehin R, Muga A, Martinez A: Tyrosine hydroxylase binds tetrahydrobiopterin cofactor with negative cooperativity, as shown by kinetic analyses and surface plasmon resonance detection. Eur J Biochem. 1999 Jun;262(3):840-9. Pubmed
  3. Ichinose H, Ohye T, Suzuki T, Inagaki H, Nagatsu T: [The relation between metabolism of biopterin and dystonia-parkinsonism] Nihon Shinkei Seishin Yakurigaku Zasshi. 1999 Apr;19(2):85-9. Pubmed
  4. Schwarz EJ, Alexander GM, Prockop DJ, Azizi SA: Multipotential marrow stromal cells transduced to produce L-DOPA: engraftment in a rat model of Parkinson disease. Hum Gene Ther. 1999 Oct 10;10(15):2539-49. Pubmed
  5. Schallreuter KU: A review of recent advances on the regulation of pigmentation in the human epidermis. Cell Mol Biol (Noisy-le-grand). 1999 Nov;45(7):943-9. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

4. Tryptophan 5-hydroxylase 1

Pharmacological action: yes
Actions: cofactor
Organism class: human
UniProt ID: P17752 Link_out
Gene: TPH1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chamas F, Serova L, Sabban EL: Tryptophan hydroxylase mRNA levels are elevated by repeated immobilization stress in rat raphe nuclei but not in pineal gland. Neurosci Lett. 1999 Jun 4;267(3):157-60. Pubmed
  2. Martinez A, Knappskog PM, Haavik J: A structural approach into human tryptophan hydroxylase and its implications for the regulation of serotonin biosynthesis. Curr Med Chem. 2001 Jul;8(9):1077-91. Pubmed
  3. Ikemoto K, Suzuki T, Ichinose H, Ohye T, Nishimura A, Nishi K, Nagatsu I, Nagatsu T: Localization of sepiapterin reductase in the human brain. Brain Res. 2002 Nov 8;954(2):237-46. Pubmed
  4. Serova LI, Maharjan S, Huang A, Sun D, Kaley G, Sabban EL: Response of tyrosine hydroxylase and GTP cyclohydrolase I gene expression to estrogen in brain catecholaminergic regions varies with mode of administration. Brain Res. 2004 Jul 23;1015(1-2):1-8. Pubmed
  5. Haavik J: [From butterflies to neurobiology and the diagnosis of AIDS. The 100th anniversary of the discovery of pteridines] Tidsskr Nor Laegeforen. 1989 Jun 30;109(19-21):1986-9. Pubmed
Enzymes

1. Prostaglandin G/H synthase 2

Actions: inducer

May have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity

UniProt ID: P35354 Link_out
Gene: PTGS2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chae SW, Bang YJ, Kim KM, Lee KY, Kang BY, Kim EM, Inoue H, Hwang O, Choi HJ: Role of cyclooxygenase-2 in tetrahydrobiopterin-induced dopamine oxidation. Biochem Biophys Res Commun. 2007 Aug 3;359(3):735-41. Epub 2007 Jun 4. Pubmed]
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19