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Record Information
StatusExpected but not Quantified
Creation Date2012-10-30 10:32:48 UTC
Update Date2017-12-20 20:19:43 UTC
Secondary Accession Numbers
  • HMDB59658
Metabolite Identification
Common NameL-erythro-tetrahydrobiopterin
DescriptionL-erythro-tetrahydrobiopterin, also known as 5,6,7,8-tetrahydrobiopterin or trihydroxybutyrophenone, belongs to biopterins and derivatives class of compounds. Those are coenzymes containing a 2-amino-pteridine-4-one derivative. They are mainly synthesized in several parts of the body, including the pineal gland. L-erythro-tetrahydrobiopterin is slightly soluble (in water) and a very weakly acidic compound (based on its pKa). L-erythro-tetrahydrobiopterin exists in all living organisms, ranging from bacteria to humans. In humans, L-erythro-tetrahydrobiopterin is involved in the phenylalanine and tyrosine metabolism. L-erythro-tetrahydrobiopterin is also involved in few metabolic disorders, which include phenylketonuria, tyrosinemia type 2 (or richner-hanhart syndrome), and tyrosinemia type 3 (TYRO3). L-erythro-tetrahydrobiopterin is a drug which is used for the treatment of tetrahydrobiopterin (bh4) deficiency. 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 (DrugBank). L-erythro-tetrahydrobiopterin is part of the Folate biosynthesis pathway. It is a substrate for: Sepiapterin reductase..
5,6,7,8-Tetrahydrobiopterin, (S-(r*,s*))-isomerMeSH
Phenylalanine hydroxylase cofactorMeSH
Sapropterin dihydrochlorideMeSH
Chemical FormulaC9H15N5O3
Average Molecular Weight241.2471
Monoisotopic Molecular Weight241.117489371
IUPAC Name(6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-3,4,5,6,7,8-hexahydropteridin-4-one
Traditional Name6R-5,6,7,8-tetrahydrobiopterin
CAS Registry NumberNot Available
InChI Identifier
Chemical 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
  • Biopterin
  • Aminopyrimidine
  • Pyrimidone
  • Secondary aliphatic/aromatic amine
  • Pyrimidine
  • 1,3-aminoalcohol
  • Vinylogous amide
  • Heteroaromatic compound
  • Secondary alcohol
  • 1,2-diol
  • 1,2-aminoalcohol
  • Secondary amine
  • Azacycle
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Amine
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors

Naturally occurring process:


Industrial application:

Physical Properties
Experimental Properties
Melting PointNot AvailableNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Predicted Properties
Water Solubility2.83 g/LALOGPS
pKa (Strongest Acidic)11.12ChemAxon
pKa (Strongest Basic)4.61ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area132 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity68.63 m³·mol⁻¹ChemAxon
Polarizability23.61 ųChemAxon
Number of Rings2ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectrum TypeDescriptionSplash Key
GC-MSGC-MS Spectrum - GC-MS (6 TMS)splash10-0zfr-2921300000-63bf6ee58b9df85919f6View in MoNA
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-0zfr-2921300000-63bf6ee58b9df85919f6View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0005-9810000000-1bfd11724596b460cae9View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-014i-6945000000-07faa91218e86d3bfe0dView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-006x-0090000000-e6b01d1139ccb3c6338dView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0gi3-0980000000-8963ef41f1138b05a813View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00xr-1900000000-bcfa359703563c696c0fView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0006-0390000000-4810efa20f31adea3824View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-006y-1930000000-5b32feeb643e238bb159View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-9400000000-a7dbebeb1df4ea110948View in MoNA
Biological Properties
Cellular LocationsNot Available
Biospecimen LocationsNot Available
Tissue LocationNot Available
Phenylalanine and Tyrosine MetabolismThumbThumb?image type=greyscaleThumb?image type=simpleMap00360
PhenylketonuriaThumbThumb?image type=greyscaleThumb?image type=simpleNot Available
Tyrosinemia Type 2 (or Richner-Hanhart syndrome)ThumbThumb?image type=greyscaleThumb?image type=simpleNot Available
Tyrosinemia Type 3 (TYRO3)ThumbThumb?image type=greyscaleThumb?image type=simpleNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDNot Available
Phenol Explorer Compound IDNot Available
FoodDB IDNot Available
KNApSAcK IDC00018229
Chemspider ID40270
KEGG Compound IDC00272
BioCyc IDCPD-14053
BiGG IDNot Available
Wikipedia LinkSapropterin
METLIN IDNot Available
PubChem Compound44257
PDB IDNot Available
ChEBI ID59560
Synthesis ReferenceNot Available
Material Safety Data Sheet (MSDS)Not Available
General References
  1. Kaufman S: Biopterin-responsive hyperphenylalaninemia. J Nutr Sci Vitaminol (Tokyo). 1992;Spec No:601-6. [PubMed:1297822 ]
  2. Sanford M, Keating GM: Spotlight on sapropterin in primary hyperphenylalaninemia. BioDrugs. 2009;23(3):201-2. doi: 10.2165/00063030-200923030-00007. [PubMed:19627172 ]
  3. MacDonald A, Ahring K, Dokoupil K, Gokmen-Ozel H, Lammardo AM, Motzfeldt K, Robert M, Rocha JC, van Rijn M, Belanger-Quintana A: Adjusting diet with sapropterin in phenylketonuria: what factors should be considered? Br J Nutr. 2011 Jul;106(2):175-82. doi: 10.1017/S0007114511000298. [PubMed:21466737 ]
  4. Burton BK, Nowacka M, Hennermann JB, Lipson M, Grange DK, Chakrapani A, Trefz F, Dorenbaum A, Imperiale M, Kim SS, Fernhoff PM: Safety of extended treatment with sapropterin dihydrochloride in patients with phenylketonuria: results of a phase 3b study. Mol Genet Metab. 2011 Aug;103(4):315-22. doi: 10.1016/j.ymgme.2011.03.020. Epub 2011 Mar 31. [PubMed:21646032 ]
  5. Utz JR, Lorentz CP, Markowitz D, Rudser KD, Diethelm-Okita B, Erickson D, Whitley CB: START, a double blind, placebo-controlled pharmacogenetic test of responsiveness to sapropterin dihydrochloride in phenylketonuria patients. Mol Genet Metab. 2012 Feb;105(2):193-7. doi: 10.1016/j.ymgme.2011.10.014. Epub 2011 Oct 29. [PubMed:22112818 ]
  6. Gordon P, Thomas JA, Suter R, Jurecki E: Evolving patient selection and clinical benefit criteria for sapropterin dihydrochloride (Kuvan(R)) treatment of PKU patients. Mol Genet Metab. 2012 Apr;105(4):672-6. doi: 10.1016/j.ymgme.2011.12.023. Epub 2012 Jan 8. [PubMed:22310224 ]
  7. Leuret O, Barth M, Kuster A, Eyer D, de Parscau L, Odent S, Gilbert-Dussardier B, Feillet F, Labarthe F: Efficacy and safety of BH4 before the age of 4 years in patients with mild phenylketonuria. J Inherit Metab Dis. 2012 Nov;35(6):975-81. doi: 10.1007/s10545-012-9464-3. Epub 2012 Mar 3. [PubMed:22388642 ]
  8. Ziesch B, Weigel J, Thiele A, Mutze U, Rohde C, Ceglarek U, Thiery J, Kiess W, Beblo S: Tetrahydrobiopterin (BH4) in PKU: effect on dietary treatment, metabolic control, and quality of life. J Inherit Metab Dis. 2012 Nov;35(6):983-92. doi: 10.1007/s10545-012-9458-1. Epub 2012 Mar 6. [PubMed:22391997 ]
  9. Cunningham A, Bausell H, Brown M, Chapman M, DeFouw K, Ernst S, McClure J, McCune H, O'Steen D, Pender A, Skrabal J, Wessel A, Jurecki E, Shediac R, Prasad S, Gillis J, Cederbaum S: Recommendations for the use of sapropterin in phenylketonuria. Mol Genet Metab. 2012 Jul;106(3):269-76. doi: 10.1016/j.ymgme.2012.04.004. Epub 2012 Apr 13. [PubMed:22575621 ]
  10. Shintaku H, Ohwada M: Long-term follow-up of tetrahydrobiopterin therapy in patients with tetrahydrobiopterin deficiency in Japan. Brain Dev. 2013 May;35(5):406-10. doi: 10.1016/j.braindev.2012.06.010. Epub 2012 Jul 24. [PubMed:22832064 ]
  11. Somaraju UR, Merrin M: Sapropterin dihydrochloride for phenylketonuria. Cochrane Database Syst Rev. 2012 Dec 12;12:CD008005. doi: 10.1002/14651858.CD008005.pub3. [PubMed:23235653 ]
  12. Gokmen Ozel H, Lammardo AM, Motzfeldt K, Robert M, Rocha JC, van Rijn M, Ahring K, Belanger-Quintana A, MacDonald A, Dokoupil K: Use of sapropterin in the management of phenylketonuria: seven case reports. Mol Genet Metab. 2013 Feb;108(2):109-11. doi: 10.1016/j.ymgme.2012.11.012. Epub 2012 Nov 28. [PubMed:23266371 ]
  13. Thiele AG, Weigel JF, Ziesch B, Rohde C, Mutze U, Ceglarek U, Thiery J, Muller AS, Kiess W, Beblo S: Nutritional Changes and Micronutrient Supply in Patients with Phenylketonuria Under Therapy with Tetrahydrobiopterin (BH(4)). JIMD Rep. 2013;9:31-40. doi: 10.1007/8904_2012_176. Epub 2012 Oct 17. [PubMed:23430545 ]
  14. Cerone R, Andria G, Giovannini M, Leuzzi V, Riva E, Burlina A: Testing for tetrahydrobiopterin responsiveness in patients with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency. Adv Ther. 2013 Mar;30(3):212-28. doi: 10.1007/s12325-013-0011-x. Epub 2013 Feb 20. [PubMed:23436109 ]
  15. Keil S, Anjema K, van Spronsen FJ, Lambruschini N, Burlina A, Belanger-Quintana A, Couce ML, Feillet F, Cerone R, Lotz-Havla AS, Muntau AC, Bosch AM, Meli CA, Billette de Villemeur T, Kern I, Riva E, Giovannini M, Damaj L, Leuzzi V, Blau N: Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study. Pediatrics. 2013 Jun;131(6):e1881-8. doi: 10.1542/peds.2012-3291. Epub 2013 May 20. [PubMed:23690520 ]
  16. Blau N: Sapropterin dihydrochloride for the treatment of hyperphenylalaninemias. Expert Opin Drug Metab Toxicol. 2013 Sep;9(9):1207-18. doi: 10.1517/17425255.2013.804064. Epub 2013 May 27. [PubMed:23705856 ]
  17. Douglas TD, Jinnah HA, Bernhard D, Singh RH: The effects of sapropterin on urinary monoamine metabolites in phenylketonuria. Mol Genet Metab. 2013 Jul;109(3):243-50. doi: 10.1016/j.ymgme.2013.04.017. Epub 2013 May 1. [PubMed:23712020 ]
  18. Stanhewicz AE, Alexander LM, Kenney WL: Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms. J Appl Physiol (1985). 2013 Oct 1;115(7):972-8. doi: 10.1152/japplphysiol.00481.2013. Epub 2013 Jun 6. [PubMed:23743404 ]


General function:
Involved in monooxygenase activity
Specific function:
Plays an important role in the physiology of adrenergic neurons.
Gene Name:
Uniprot ID:
Molecular weight:
L-Tyrosine + L-erythro-tetrahydrobiopterin + Oxygen → L-Dopa + 4a-Hydroxytetrahydrobiopterindetails
L-erythro-tetrahydrobiopterin + L-Tyrosine + Oxygen → L-Dopa + 4a-Carbinolamine tetrahydrobiopterin + Waterdetails
General function:
Involved in amino acid binding
Specific function:
Not Available
Gene Name:
Uniprot ID:
Molecular weight:
L-Phenylalanine + L-erythro-tetrahydrobiopterin + Oxygen → L-Tyrosine + 4a-Hydroxytetrahydrobiopterindetails
L-erythro-tetrahydrobiopterin + L-Phenylalanine + Oxygen → 4a-Carbinolamine tetrahydrobiopterin + L-Tyrosine + Waterdetails
General function:
Involved in oxidoreductase activity
Specific function:
Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.
Gene Name:
Uniprot ID:
Molecular weight:
L-erythro-tetrahydrobiopterin + NADP → Dyspropterin + NADPHdetails
L-erythro-tetrahydrobiopterin + NADP → 6-Lactoyltetrahydropterin + NADPH + Hydrogen Iondetails
General function:
Involved in amino acid binding
Specific function:
Not Available
Gene Name:
Uniprot ID:
Molecular weight:
L-Tryptophan + L-erythro-tetrahydrobiopterin + Oxygen → Oxitriptan + 4a-Hydroxytetrahydrobiopterindetails
L-erythro-tetrahydrobiopterin + L-Tryptophan + Oxygen → Oxitriptan + 4a-Carbinolamine tetrahydrobiopterin + Waterdetails
General function:
Involved in amino acid binding
Specific function:
Not Available
Gene Name:
Uniprot ID:
Molecular weight:
L-Tryptophan + L-erythro-tetrahydrobiopterin + Oxygen → Oxitriptan + 4a-Hydroxytetrahydrobiopterindetails
L-erythro-tetrahydrobiopterin + L-Tryptophan + Oxygen → Oxitriptan + 4a-Carbinolamine tetrahydrobiopterin + Waterdetails
General function:
Involved in oxidoreductase activity
Specific function:
The product of this enzyme, tetrahydrobiopterin (BH-4), is an essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases.
Gene Name:
Uniprot ID:
Molecular weight:
4a-Carbinolamine tetrahydrobiopterin + NADH + Hydrogen Ion → L-erythro-tetrahydrobiopterin + NADdetails
4a-Carbinolamine tetrahydrobiopterin + NADPH + Hydrogen Ion → L-erythro-tetrahydrobiopterin + NADPdetails
General function:
Not Available
Specific function:
Glyceryl-ether monooxygenase that cleaves the O-alkyl bond of ether lipids. Ether lipids are essential components of brain membranes.
Gene Name:
Uniprot ID:
Molecular weight:
1-alkyl-sn-glycerol + L-erythro-tetrahydrobiopterin + Oxygen → 1-O-alkyl-sn-glycerol + Dihydrobiopterin + Waterdetails