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Identification
NameSapropterin
Accession NumberDB00360  (APRD01297)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Sapropterin (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
2-Amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydoro-4(1H)-pteridinone
5,6,7,8 tetrahydrobiopterin
5,6,7,8-tetrahydrobiopterin
6R-5,6,7,8-tetrahydrobiopterin
6R-BH4
6R-L-5,6,7,8-tetrahydrobiopterin
L-erythro-tetrahydrobiopterin
R-THBP
Tetrahydrobiopterin
External Identifiers
  • 17528-72-2
  • 27070-47-9
  • R-THBP
  • Sun 0588
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Kuvantablet100 mg/1oralBio Marin Pharmaceutical Inc.2007-12-142016-04-05Us
Kuvantablet100 mgoralBiomarin Pharmaceutical Inc2010-07-05Not applicableCanada
Kuvanpowder, for solution500 mg/1oralBio Marin Pharmaceutical Inc.2015-05-272016-04-05Us
Kuvanpowder, for solution100 mg/1oralBio Marin Pharmaceutical Inc.2014-02-212016-04-05Us
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
BH4Excelsior
BioptenDaiichi Sankyo
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Sapropterin dihydrochloride
69056-38-8
Thumb
  • InChI Key: RKSUYBCOVNCALL-NTVURLEBSA-N
  • Monoisotopic Mass: 313.0708448
  • Average Mass: 314.17
DBSALT001133
Categories
UNIIEGX657432I
CAS number62989-33-7
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.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Tryptophan MetabolismMetabolicSMP00063
Tyrosinemia Type IDiseaseSMP00218
Disulfiram Action PathwayDrug actionSMP00429
Arginine and Proline MetabolismMetabolicSMP00020
Prolinemia Type IIDiseaseSMP00208
Hyperprolinemia Type IDiseaseSMP00361
Dopa-responsive dystoniaDiseaseSMP00486
Hyperphenylalaniemia due to guanosine triphosphate cyclohydrolase deficiencyDiseaseSMP00487
Hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency (ptps)DiseaseSMP00488
Pterine BiosynthesisMetabolicSMP00005
Tyrosine MetabolismMetabolicSMP00006
Prolidase Deficiency (PD)DiseaseSMP00207
Segawa syndromeDiseaseSMP00490
Tyrosinemia, transient, of the newbornDiseaseSMP00494
AlkaptonuriaDiseaseSMP00169
HawkinsinuriaDiseaseSMP00190
Ornithine Aminotransferase Deficiency (OAT Deficiency)DiseaseSMP00363
Hyperphenylalaninemia due to dhpr-deficiencyDiseaseSMP00489
Dopamine beta-hydroxylase deficiencyDiseaseSMP00498
Monoamine oxidase-a deficiency (MAO-A)DiseaseSMP00533
Guanidinoacetate Methyltransferase Deficiency (GAMT Deficiency)DiseaseSMP00188
Hyperprolinemia Type IIDiseaseSMP00360
Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency)DiseaseSMP00362
Sepiapterin reductase deficiencyDiseaseSMP00491
Creatine deficiency, guanidinoacetate methyltransferase deficiencyDiseaseSMP00504
Hyperornithinemia with gyrate atrophy (HOGA)DiseaseSMP00505
Hyperornithinemia-hyperammonemia-homocitrullinuria [HHH-syndrome]DiseaseSMP00506
L-arginine:glycine amidinotransferase deficiencyDiseaseSMP00507
Doxorubicin Metabolism PathwayDrug metabolismSMP00650
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 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Biomarin pharmaceutical inc
Packagers
Dosage forms
FormRouteStrength
Powder, for solutionoral100 mg/1
Powder, for solutionoral500 mg/1
Tabletoral100 mg/1
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
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2545968 No2010-03-092024-11-17Canada
US7566462 Yes2006-05-162026-05-16Us
US7566714 Yes2005-05-172025-05-17Us
US7612073 Yes2005-05-172025-05-17Us
US7727987 Yes2005-05-172025-05-17Us
US7947681 Yes2005-05-172025-05-17Us
US8003126 Yes2006-05-162026-05-16Us
US8067416 Yes2005-05-172025-05-17Us
US8318745 Yes2005-05-172025-05-17Us
US9216178 No2012-11-012032-11-01Us
USRE43797 Yes2005-05-172025-05-17Us
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 References
  1. Thony B, Auerbach G, Blau N: Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J. 2000 Apr 1;347 Pt 1:1-16. [PubMed:10727395 ]
External Links
ATC CodesA16AX07
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AvanafilTetrahydrobiopterin may increase the hypotensive activities of Avanafil.
LevodopaThe risk or severity of adverse effects can be increased when Tetrahydrobiopterin is combined with Levodopa.
MethotrexateThe serum concentration of Tetrahydrobiopterin can be decreased when it is combined with Methotrexate.
PralatrexateThe serum concentration of Tetrahydrobiopterin can be decreased when it is combined with Pralatrexate.
SildenafilTetrahydrobiopterin may increase the hypotensive activities of Sildenafil.
TadalafilTetrahydrobiopterin may increase the hypotensive activities of Tadalafil.
VardenafilTetrahydrobiopterin may increase the hypotensive activities of Vardenafil.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
cofactor
General Function:
Tetrahydrobiopterin binding
Specific Function:
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.Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by ...
Gene Name:
NOS3
Uniprot ID:
P29474
Molecular Weight:
133287.62 Da
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:10075731 ]
  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:10749876 ]
  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:10924132 ]
  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:10995244 ]
  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:11009561 ]
  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:12003347 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
cofactor
General Function:
Phenylalanine 4-monooxygenase activity
Specific Function:
Not Available
Gene Name:
PAH
Uniprot ID:
P00439
Molecular Weight:
51861.565 Da
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:10089284 ]
  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:10839989 ]
  3. Fitzpatrick PF: Tetrahydropterin-dependent amino acid hydroxylases. Annu Rev Biochem. 1999;68:355-81. [PubMed:10872454 ]
  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:10924272 ]
  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:11163771 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
cofactor
General Function:
Tyrosine 3-monooxygenase activity
Specific Function:
Plays an important role in the physiology of adrenergic neurons.
Gene Name:
TH
Uniprot ID:
P07101
Molecular Weight:
58599.545 Da
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:10197775 ]
  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:10411647 ]
  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:10464780 ]
  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:10543618 ]
  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:10643998 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
cofactor
General Function:
Tryptophan 5-monooxygenase activity
Specific Function:
Not Available
Gene Name:
TPH1
Uniprot ID:
P17752
Molecular Weight:
50984.725 Da
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:10381000 ]
  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:11472242 ]
  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:12414107 ]
  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:15223360 ]
  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:2665179 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inducer
General Function:
Prostaglandin-endoperoxide synthase activity
Specific Function:
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, p...
Gene Name:
PTGS2
Uniprot ID:
P35354
Molecular Weight:
68995.625 Da
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:17560944 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on May 06, 2016 03:14