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Identification
NameTetrahydrobiopterin
Accession NumberDB00360  (APRD01297)
TypeSmall Molecule
GroupsApproved, Investigational
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
Synonyms
SynonymLanguageCode
(6R)-2-Amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydropteridin-4(1H)-oneNot AvailableIUPAC
2-Amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydoro-4(1H)-pteridinoneNot AvailableNot Available
5,6,7,8 TetrahydrobiopterinNot AvailableNot Available
5,6,7,8-TetrahydrobiopterinNot AvailableNot Available
BH4Not AvailableNot Available
sapropterinNot AvailableINN
TetrahydrobiopterinNot AvailableNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Kuvantablet100 mgoralBio Marin Pharmaceutical Inc.2007-12-14Not AvailableUs
Kuvanpowder, for solution100 mgoralBio Marin Pharmaceutical Inc.2014-02-21Not AvailableUs
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
BH4Excelsior
BioptenDaiichi Sankyo
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number17528-72-2
WeightAverage: 241.2471
Monoisotopic: 241.117489371
Chemical FormulaC9H15N5O3
InChI KeyFNKQXYHWGSIFBK-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)
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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as biopterins and derivatives. These are coenzymes containing a 2-amino-pteridine-4-one derivative. They are mainly synthesized in several parts of the body, including the pineal gland.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPteridines and derivatives
Sub ClassPterins and derivatives
Direct ParentBiopterins and derivatives
Alternative Parents
Substituents
  • Biopterin
  • Secondary aliphatic/aromatic amine
  • Pyrimidone
  • Imidolactam
  • Pyrimidine
  • Primary aromatic amine
  • Heteroaromatic compound
  • Vinylogous amide
  • 1,3-aminoalcohol
  • Secondary alcohol
  • Lactam
  • 1,2-diol
  • 1,2-aminoalcohol
  • Azacycle
  • Secondary amine
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of tetrahydrobiopterin (BH4) deficiency.
PharmacodynamicsTetrahydrobiopterin (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 actionTetrahydrobiopterin (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.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Hyperphenylalaninemia due to dhpr-deficiencyDiseaseSMP00489
Segawa syndromeDiseaseSMP00490
Hyperphenylalaniemia due to guanosine triphosphate cyclohydrolase deficiencyDiseaseSMP00487
Hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency (ptps)DiseaseSMP00488
Pterine BiosynthesisMetabolicSMP00005
Dopa-responsive dystoniaDiseaseSMP00486
Sepiapterin reductase deficiencyDiseaseSMP00491
Doxorubicin Metabolism PathwayDrug metabolismSMP00650
Hyperprolinemia Type IIDiseaseSMP00360
HawkinsinuriaDiseaseSMP00190
Monoamine oxidase-a deficiency (MAO-A)DiseaseSMP00533
Hyperprolinemia Type IDiseaseSMP00361
Tryptophan MetabolismMetabolicSMP00063
Tyrosinemia Type IDiseaseSMP00218
Creatine deficiency, guanidinoacetate methyltransferase deficiencyDiseaseSMP00504
Prolidase Deficiency (PD)DiseaseSMP00207
Guanidinoacetate Methyltransferase Deficiency (GAMT Deficiency)DiseaseSMP00188
Tyrosinemia, transient, of the newbornDiseaseSMP00494
Hyperornithinemia-hyperammonemia-homocitrullinuria [HHH-syndrome]DiseaseSMP00506
Arginine and Proline MetabolismMetabolicSMP00020
Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency)DiseaseSMP00362
Ornithine Aminotransferase Deficiency (OAT Deficiency)DiseaseSMP00363
Tyrosine MetabolismMetabolicSMP00006
AlkaptonuriaDiseaseSMP00169
L-arginine:glycine amidinotransferase deficiencyDiseaseSMP00507
Prolinemia Type IIDiseaseSMP00208
Dopamine beta-hydroxylase deficiencyDiseaseSMP00498
Hyperornithinemia with gyrate atrophy (HOGA)DiseaseSMP00505
Disulfiram Action PathwayDrug actionSMP00429
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9938
Blood Brain Barrier+0.5558
Caco-2 permeable-0.6674
P-glycoprotein substrateSubstrate0.785
P-glycoprotein inhibitor INon-inhibitor0.9599
P-glycoprotein inhibitor IINon-inhibitor0.9881
Renal organic cation transporterNon-inhibitor0.8946
CYP450 2C9 substrateNon-substrate0.768
CYP450 2D6 substrateNon-substrate0.78
CYP450 3A4 substrateNon-substrate0.5278
CYP450 1A2 substrateNon-inhibitor0.91
CYP450 2C9 substrateNon-inhibitor0.907
CYP450 2D6 substrateNon-inhibitor0.9231
CYP450 2C19 substrateNon-inhibitor0.9025
CYP450 3A4 substrateNon-inhibitor0.9227
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9348
Ames testNon AMES toxic0.6328
CarcinogenicityNon-carcinogens0.9271
BiodegradationNot ready biodegradable0.9607
Rat acute toxicity2.4428 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.993
hERG inhibition (predictor II)Non-inhibitor0.6937
Pharmacoeconomics
Manufacturers
  • Biomarin pharmaceutical inc
Packagers
Dosage forms
FormRouteStrength
Powder, for solutionoral100 mg
Tabletoral100 mg
Prices
Unit descriptionCostUnit
Kuvan 100 mg tablet36.5USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
Canada25459682010-03-092024-11-17
United States75664622005-11-162025-11-16
United States75667142004-11-172024-11-17
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point250-255 °C (hydrochloride salt)Not Available
water solubility>20 mg/mL (dichloride salt)Not Available
logP-1.7Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.21 mg/mLALOGPS
logP-1.7ALOGPS
logP-2.7ChemAxon
logS-2ALOGPS
pKa (Strongest Acidic)10.01ChemAxon
pKa (Strongest Basic)3.58ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area132 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity68.43 m3·mol-1ChemAxon
Polarizability23.4 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Steven S. Gross, “Blocking utilization of tetrahydrobiopterin to block induction of nitric oxide synthesis.” U.S. Patent US5502050, issued October, 1984.

US5502050
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
ATC CodesA16AX07
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Nitric oxide synthase, endothelial

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: cofactor

Components

Name UniProt ID Details
Nitric oxide synthase, endothelial P29474 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: cofactor

Components

Name UniProt ID Details
Phenylalanine-4-hydroxylase P00439 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: cofactor

Components

Name UniProt ID Details
Tyrosine 3-monooxygenase P07101 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: cofactor

Components

Name UniProt ID Details
Tryptophan 5-hydroxylase 1 P17752 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Prostaglandin G/H synthase 2 P35354 Details

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]

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:10