You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on Human Metabolome Database.
Record Information
Version3.6
Creation Date2005-11-16 15:48:42 UTC
Update Date2014-06-13 18:05:43 UTC
HMDB IDHMDB00027
Secondary Accession Numbers
  • HMDB02154
Metabolite Identification
Common NameTetrahydrobiopterin
DescriptionTetrahydrobiopterin or BH4 is a cofactor in the synthesis of nitric oxide. In fact it is used by all three human nitric-oxide synthases (NOS) eNOS, nNOS, and iNOS as well as the enzyme glyceryl-ether monooxygenase. 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. Specifically, tetrahydrobiopterin is a cofactor for tryptophan 5-hydroxylase 1, tyrosine 3-monooxygenase, and phenylalanine hydroxylase all of which are essential for the formation of the neurotransmitters dopamine, noradrenaline and adrenaline. Tetrahydrobiopterin has been proposed to be involved in promotion of neurotransmitter release in the brain and the regulation of human melanogenesis. A defect in BH4 production and/or a defect in the enzyme dihydropteridine reductase (DHPR) causes phenylketonuria type IV, as well as dopa-responsive dystonias. BH4 is also implicated in Parkinson's disease, Alzheimer's disease and depression. Tetrahydrobiopterin is present in probably every cell or tissue of higher animals. On the other hand, most bacteria, fungi and plants do not synthesize tetrahydrobiopterin. -- Wikipedia.
Structure
Thumb
Synonyms
  1. (1R,2S)-(2-Amino-3,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)-1,2-propandiol
  2. 2-Amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydoro-4(1H)-5,6,7,8-Tetrahydro-2-amino-6-(1,2-dihydroxypropyl)-4(1H)-pteridinone
  3. 2-Amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4(1H)-Pteridinone
  4. 5,6,7,8-Erythro-tetrahydrobiopterin
  5. 5,6,7,8-Tetra-H-biopterin
  6. 5,6,7,8-Tetrahydro-2-amino-6-(1,2-dihydroxypropyl)-4(1H)-pteridinone
  7. 5,6,7,8-Tetrahydrobiopterin
  8. L-Erythro-2-Amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4(3H)-pteridinon
  9. Tetra-H-biopterin
  10. Tetra-hydro-biopterin
  11. Tetrahydrobiopterin
Chemical FormulaC9H15N5O3
Average Molecular Weight241.2471
Monoisotopic Molecular Weight241.117489371
IUPAC Name2-amino-6-(1,2-dihydroxypropyl)-3,4,5,6,7,8-hexahydropteridin-4-one
Traditional NameBH4
CAS Registry Number17528-72-2
SMILES
CC(O)C(O)C1CNC2=C(N1)C(=O)NC(N)=N2
InChI Identifier
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)
InChI KeyFNKQXYHWGSIFBK-UHFFFAOYSA-N
Chemical Taxonomy
KingdomOrganic Compounds
Super ClassAromatic Heteropolycyclic Compounds
ClassPteridines and Derivatives
Sub ClassPterins and Derivatives
Other Descriptors
  • Pterins and Derivatives
  • a biopterin(Cyc)
  • biopterins(ChEBI)
  • tetrahydropterin(ChEBI)
Substituents
  • 1,2 Aminoalcohol
  • 1,2 Diol
  • 1,3 Aminoalcohol
  • Aminopyrimidine
  • Pyrimidine
  • Pyrimidone
  • Secondary Alcohol
Direct ParentBiopterins and Derivatives
Ontology
StatusDetected and Quantified
Origin
  • Endogenous
Biofunction
  • Component of Phenylalanine, tyrosine and tryptophan biosynthesis
  • Component of Tryptophan metabolism
  • Component of Tyrosine metabolism
  • Enzyme co-factor
ApplicationNot Available
Cellular locations
  • Nucleus
Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting Point250 - 255 °C (hydrochloride salt)Not Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Predicted Properties
PropertyValueSource
Water Solubility2.03ALOGPS
logP-1.8ALOGPS
logP-2.3ChemAxon
logS-2.1ALOGPS
pKa (Strongest Acidic)11.12ChemAxon
pKa (Strongest Basic)4.61ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area132 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity68.63 m3·mol-1ChemAxon
Polarizability23.53 Å3ChemAxon
Spectra
SpectraNot Available
Biological Properties
Cellular Locations
  • Nucleus
Biofluid Locations
  • Blood
  • Cerebrospinal Fluid (CSF)
Tissue Location
  • All Tissues
Pathways
NameSMPDB LinkKEGG Link
Pterine BiosynthesisSMP00005map00790
Normal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodDetected and Quantified0.0093 +/- 0.0005 uMAdult (>18 years old)BothNormal details
Abnormal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodDetected and Quantified0.16 (0.0-5.8) uMAdult (>18 years old)Both
Septic shock
details
BloodDetected and Quantified1.2 (0.8-14.9) uMAdult (>18 years old)Both
Septic shock
details
BloodDetected and Quantified0.0044 +/- 0.0007 uMAdult (>18 years old)Both
Myocardial infarction
details
Cerebrospinal Fluid (CSF)Detected and Quantified14400.0 uMNewborn (0-30 days old)BothGeneralized seizures details
Associated Disorders and Diseases
Disease References
Septic shock
  1. Galley HF, Le Cras AE, Yassen K, Grant IS, Webster NR: Circulating tetrahydrobiopterin concentrations in patients with septic shock. Br J Anaesth. 2001 Apr;86(4):578-80. Pubmed: 11573638
Epilepsy
  1. Cady EB, Lorek A, Penrice J, Reynolds EO, Iles RA, Burns SP, Coutts GA, Cowan FM: Detection of propan-1,2-diol in neonatal brain by in vivo proton magnetic resonance spectroscopy. Magn Reson Med. 1994 Dec;32(6):764-7. Pubmed: 7869898
Myocardial infarction
  1. Yada T, Kaji S, Akasaka T, Mochizuki S, Ogasawara Y, Tanemoto K, Yoshida K, Kajiya F: Changes of asymmetric dimethylarginine, nitric oxide, tetrahydrobiopterin, and oxidative stress in patients with acute myocardial infarction by medical treatments. Clin Hemorheol Microcirc. 2007;37(3):269-76. Pubmed: 17726257
Associated OMIM IDsNone
DrugBank IDNot Available
DrugBank Metabolite IDNot Available
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDFDB021880
KNApSAcK IDNot Available
Chemspider ID1093
KEGG Compound IDC00272
BioCyc IDTETRA-H-BIOPTERIN
BiGG ID34464
Wikipedia LinkTetrahydrobiopterin
NuGOwiki LinkHMDB00027
Metagene LinkHMDB00027
METLIN ID5098
PubChem Compound1125
PDB ID1DF1
ChEBI ID15372
References
Synthesis ReferenceHe, Aimin. The function and biosynthesis of tetrahydrobiopterin in nocardia. (2002), 123 pp.
Material Safety Data Sheet (MSDS)Download (PDF)
General References
  1. Furukawa Y, Kish SJ, Bebin EM, Jacobson RD, Fryburg JS, Wilson WG, Shimadzu M, Hyland K, Trugman JM: Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations. Ann Neurol. 1998 Jul;44(1):10-6. Pubmed: 9667588
  2. Curtius HC, Heintel D, Ghisla S, Kuster T, Leimbacher W, Niederwieser A: Tetrahydrobiopterin biosynthesis. Studies with specifically labeled (2H)NAD(P)H and 2H2O and of the enzymes involved. Eur J Biochem. 1985 May 2;148(3):413-9. Pubmed: 3888618
  3. Galley HF, Le Cras AE, Yassen K, Grant IS, Webster NR: Circulating tetrahydrobiopterin concentrations in patients with septic shock. Br J Anaesth. 2001 Apr;86(4):578-80. Pubmed: 11573638
  4. Kuhn DM, Geddes TJ: Tetrahydrobiopterin prevents nitration of tyrosine hydroxylase by peroxynitrite and nitrogen dioxide. Mol Pharmacol. 2003 Oct;64(4):946-53. Pubmed: 14500751
  5. Takikawa S, Curtius HC, Redweik U, Leimbacher W, Ghisla S: Biosynthesis of tetrahydrobiopterin. Purification and characterization of 6-pyruvoyl-tetrahydropterin synthase from human liver. Eur J Biochem. 1986 Dec 1;161(2):295-302. Pubmed: 3536512
  6. Walter R, Kaufmann PA, Buck A, Berthold T, Wyss C, von Schulthess GK, Schaffner A, Schoedon G: Tetrahydrobiopterin increases myocardial blood flow in healthy volunteers: a double-blind, placebo-controlled study. Swiss Med Wkly. 2001 Feb 24;131(7-8):91-4. Pubmed: 11416883
  7. Hyland K, Gunasekara RS, Munk-Martin TL, Arnold LA, Engle T: The hph-1 mouse: a model for dominantly inherited GTP-cyclohydrolase deficiency. Ann Neurol. 2003;54 Suppl 6:S46-8. Pubmed: 12891653
  8. Leeming RJ, Blair JA, Melikian V, O'Gorman DJ: Biopterin derivatives in human body fluids and tissues. J Clin Pathol. 1976 May;29(5):444-51. Pubmed: 932231
  9. Schallreuter KU, Moore J, Wood JM, Beazley WD, Peters EM, Marles LK, Behrens-Williams SC, Dummer R, Blau N, Thony B: Epidermal H(2)O(2) accumulation alters tetrahydrobiopterin (6BH4) recycling in vitiligo: identification of a general mechanism in regulation of all 6BH4-dependent processes? J Invest Dermatol. 2001 Jan;116(1):167-74. Pubmed: 11168813
  10. Dhondt JL, Cotton RG, Danks DM: Liver enzyme activities in hyperphenylalaninaemia due to a defective synthesis of tetrahydrobiopterin. J Inherit Metab Dis. 1985;8(2):47-8. Pubmed: 3939528
  11. Sawabe K, Suetake Y, Nakanishi N, Wakasugi KO, Hasegawa H: Cellular accumulation of tetrahydrobiopterin following its administration is mediated by two different processes; direct uptake and indirect uptake mediated by a methotrexate-sensitive process. Mol Genet Metab. 2005 Dec;86 Suppl 1:S133-8. Epub 2005 Sep 13. Pubmed: 16165391
  12. Koch R, Moseley KD, Moats R, Yano S, Matalon R, Guttler F: Danger of high-protein dietary supplements to persons with hyperphenylalaninaemia. J Inherit Metab Dis. 2003;26(4):339-42. Pubmed: 12971421
  13. Cady EB, Lorek A, Penrice J, Reynolds EO, Iles RA, Burns SP, Coutts GA, Cowan FM: Detection of propan-1,2-diol in neonatal brain by in vivo proton magnetic resonance spectroscopy. Magn Reson Med. 1994 Dec;32(6):764-7. Pubmed: 7869898
  14. Matter H, Kumar HS, Fedorov R, Frey A, Kotsonis P, Hartmann E, Frohlich LG, Reif A, Pfleiderer W, Scheurer P, Ghosh DK, Schlichting I, Schmidt HH: Structural analysis of isoform-specific inhibitors targeting the tetrahydrobiopterin binding site of human nitric oxide synthases. J Med Chem. 2005 Jul 28;48(15):4783-92. Pubmed: 16033258
  15. Kaufman S, Kapatos G, Rizzo WB, Schulman JD, Tamarkin L, Van Loon GR: Tetrahydropterin therapy for hyperphenylalaninemia caused by defective synthesis of tetrahydrobiopterin. Ann Neurol. 1983 Sep;14(3):308-15. Pubmed: 6139056
  16. Spaapen LJ, Bakker JA, Velter C, Loots W, Rubio-Gozalbo ME, Forget PP, Dorland L, De Koning TJ, Poll-The BT, Ploos van Amstel HK, Bekhof J, Blau N, Duran M: Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates. J Inherit Metab Dis. 2001 Jun;24(3):352-8. Pubmed: 11486900

Enzymes

General function:
Involved in oxidoreductase activity
Specific function:
This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds. Catalyzes the rate-limiting conversions of tyrosine to DOPA, DOPA to DOPA-quinone and possibly 5,6-dihydroxyindole to indole-5,6 quinone.
Gene Name:
TYR
Uniprot ID:
P14679
Molecular weight:
60392.69
References
  1. Wood JM, Schallreuter-Wood KU, Lindsey NJ, Callaghan S, Gardner ML: A specific tetrahydrobiopterin binding domain on tyrosinase controls melanogenesis. Biochem Biophys Res Commun. 1995 Jan 17;206(2):480-5. Pubmed: 7826365
General function:
Involved in monooxygenase activity
Specific function:
Plays an important role in the physiology of adrenergic neurons.
Gene Name:
TH
Uniprot ID:
P07101
Molecular weight:
55611.26
References
  1. Madsen JT, Jansen P, Hesslinger C, Meyer M, Zimmer J, Gramsbergen JB: Tetrahydrobiopterin precursor sepiapterin provides protection against neurotoxicity of 1-methyl-4-phenylpyridinium in nigral slice cultures. J Neurochem. 2003 Apr;85(1):214-23. Pubmed: 12641743
General function:
Involved in amino acid binding
Specific function:
Not Available
Gene Name:
PAH
Uniprot ID:
P00439
Molecular weight:
51861.565
References
  1. Andersen OA, Flatmark T, Hough E: High resolution crystal structures of the catalytic domain of human phenylalanine hydroxylase in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin. J Mol Biol. 2001 Nov 23;314(2):279-91. Pubmed: 11718561
General function:
Involved in 6-pyruvoyltetrahydropterin synthase activity
Specific function:
Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases. Catalyzes the transformation of 7,8-dihydroneopterin triphosphate into 6-pyruvoyl tetrahydropterin.
Gene Name:
PTS
Uniprot ID:
Q03393
Molecular weight:
16385.63
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:
SPR
Uniprot ID:
P35270
Molecular weight:
28048.13
References
  1. Auerbach G, Nar H: The pathway from GTP to tetrahydrobiopterin: three-dimensional structures of GTP cyclohydrolase I and 6-pyruvoyl tetrahydropterin synthase. Biol Chem. 1997 Mar-Apr;378(3-4):185-92. Pubmed: 9165069
General function:
Involved in amino acid binding
Specific function:
Not Available
Gene Name:
TPH1
Uniprot ID:
P17752
Molecular weight:
50984.725
References
  1. Sumi-Ichinose C, Urano F, Kuroda R, Ohye T, Kojima M, Tazawa M, Shiraishi H, Hagino Y, Nagatsu T, Nomura T, Ichinose H: Catecholamines and serotonin are differently regulated by tetrahydrobiopterin. A study from 6-pyruvoyltetrahydropterin synthase knockout mice. J Biol Chem. 2001 Nov 2;276(44):41150-60. Epub 2001 Aug 21. Pubmed: 11517215
General function:
Involved in amino acid binding
Specific function:
Not Available
Gene Name:
TPH2
Uniprot ID:
Q8IWU9
Molecular weight:
56056.295
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:
QDPR
Uniprot ID:
P09417
Molecular weight:
25789.295
References
  1. Shen RS: Inhibition of dopamine autoxidation by tetrahydrobiopterin and NADH in the presence of dihydropteridine reductase. Neurotoxicology. 1991 Summer;12(2):201-8. Pubmed: 1956581
General function:
Involved in oxidoreductase activity
Specific function:
Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such COX2.
Gene Name:
NOS2
Uniprot ID:
P35228
Molecular weight:
131116.3
General function:
Involved in oxidoreductase activity
Specific function:
Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR.
Gene Name:
NOS1
Uniprot ID:
P29475
Molecular weight:
160969.095
References
  1. Kamada Y, Jenkins GJ, Lau M, Dunbar AY, Lowe ER, Osawa Y: Tetrahydrobiopterin depletion and ubiquitylation of neuronal nitric oxide synthase. Brain Res Mol Brain Res. 2005 Dec 7;142(1):19-27. Epub 2005 Oct 10. Pubmed: 16216381
General function:
Involved in oxidoreductase activity
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 forming heterodimers with isoform 1.
Gene Name:
NOS3
Uniprot ID:
P29474
Molecular weight:
133273.59
References
  1. Shirodaria C, Antoniades C, Lee J, Jackson CE, Robson MD, Francis JM, Moat SJ, Ratnatunga C, Pillai R, Refsum H, Neubauer S, Channon KM: Global improvement of vascular function and redox state with low-dose folic acid: implications for folate therapy in patients with coronary artery disease. Circulation. 2007 May 1;115(17):2262-70. Epub 2007 Apr 9. Pubmed: 17420345
General function:
Involved in GTP cyclohydrolase I activity
Specific function:
Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown.
Gene Name:
GCH1
Uniprot ID:
P30793
Molecular weight:
27902.855
References
  1. Auerbach G, Nar H: The pathway from GTP to tetrahydrobiopterin: three-dimensional structures of GTP cyclohydrolase I and 6-pyruvoyl tetrahydropterin synthase. Biol Chem. 1997 Mar-Apr;378(3-4):185-92. Pubmed: 9165069
General function:
Involved in protein binding
Specific function:
Mediates tetrahydrobiopterin inhibition of GTP cyclohydrolase 1. This inhibition is reversed by L-phenylalanine
Gene Name:
GCHFR
Uniprot ID:
P30047
Molecular weight:
9698.2
References
  1. Kapatos G, Hirayama K, Shimoji M, Milstien S: GTP cyclohydrolase I feedback regulatory protein is expressed in serotonin neurons and regulates tetrahydrobiopterin biosynthesis. J Neurochem. 1999 Feb;72(2):669-75. Pubmed: 9930739
General function:
Involved in 4-alpha-hydroxytetrahydrobiopterin dehydratase activity
Specific function:
Involved in tetrahydrobiopterin biosynthesis. Seems to both prevent the formation of 7-pterins and accelerate the formation of quinonoid-BH2. Coactivator for HNF1A-dependent transcription. Regulates the dimerization of homeodomain protein HNF1A and enhances its transcriptional activity.
Gene Name:
PCBD1
Uniprot ID:
P61457
Molecular weight:
11999.515
References
  1. Hirayama K, Kapatos G: Expression and regulation of rat 6-pyruvoyl tetrahydropterin synthase mRNA. Neurochem Int. 1995 Jun;26(6):601-6. Pubmed: 7545485
General function:
Involved in nitric-oxide synthase activity
Specific function:
Not Available
Gene Name:
Not Available
Uniprot ID:
Q9UM94
Molecular weight:
6563.5