This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Tetrahydrobiopterin Biosynthesis|
Expected Taxonomic Range: Metazoa
tetrahydrobiopterin is a cofactor of several enzymes, including the aromatic amino acid hydroxylases tryptophan 5-hydroxylase 1, tyrosine 3-monooxygenase, and phenylalanine hydroxylase (which are essential for the formation of the neurotransmitters dopamine, (R)-noradrenaline, (R)-adrenaline and serotonin - see catecholamine biosynthesis), all three nitric-oxide synthases (NOS) eNOS, nNOS, and iNOS (see citrulline-nitric oxide cycle), and the enzyme glyceryl-ether monooxygenase.
In addition, tetrahydrobiopterin has been proposed to be involved in proliferation of murine erythrocyte cells [Tanaka89a], promotion of neurotransmitter release in the brain [Mataga91] and regulation of human melanogenesis [Schallreuter94]. Deffciency causes severe neurological disorders characterized by hyperphenylalaninaemia and monoamine neurotransmitter deffciency, and is also implicated in Parkinson's disease, Alzheimer's disease and depression ([Blau, Thony00].
Tetrahydrobiopterin is present in probably every cell or tissue of higher animals [Thony00]. On the other hand, most bacteria, fungi and plants do not synthesize tetrahydrobiopterin. However, tetrahydrobiopterin was found in glycosylated forms in some groups of bacteria including cyanobacteria [Chung00] and the anaerobic photosynthetic Chlorobium species [Cho98], and have been reported in several types of fungi [Maier95, Wang11e].
About This Pathway
While most of the tetrahydrobiopterin in mammalian cells is probably formed as described in the pathway tetrahydrobiopterin biosynthesis I, a study performed with rat brains has shown that when the activity of the enzyme sepiapterin reductase (L-threo-7,8-dihydrobiopterin forming) is limiting, a second pathway can lead to tetrahydrobiopterin production [Milstien89]. In this route, 6-pyruvoyl tetrahydropterin is converted by the enzyme 6-pyruvoyltetrahydropterin 2'-reductase to 6-lactoyl-5,6,7,8-tetrahydropterin, which is then converted to tetrahydrobiopterin by sepiapterin reductase (L-threo-7,8-dihydrobiopterin forming).
Blau: Blau N, Bonafe L, Thony B "Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency." Mol Genet Metab 74(1-2);172-85. PMID: 11592814
Cho98: Cho SH, Na JU, Youn H, Hwang CS, Lee CH, Kang SO (1998). "Tepidopterin, 1-O-(L-threo-biopterin-2'-yl)-beta-N-acetylglucosamine from Chlorobium tepidum." Biochim Biophys Acta 1379(1);53-60. PMID: 9468332
Chung00: Chung HJ, Kim YA, Kim YJ, Choi YK, Hwang YK, Park YS (2000). "Purification and characterization of UDP-glucose:tetrahydrobiopterin glucosyltransferase from Synechococcus sp. PCC 7942." Biochim Biophys Acta 1524(2-3);183-8. PMID: 11113566
Maier95: Maier J, Ninnemann H (1995). "Biosynthesis of pteridines in Neurospora crassa, Phycomyces blakesleeanus and Euglena gracilis: detection and characterization of biosynthetic enzymes." Photochem Photobiol 61(1);43-53. PMID: 7899493
Mataga91: Mataga N, Imamura K, Watanabe Y (1991). "6R-tetrahydrobiopterin perfusion enhances dopamine, serotonin, and glutamate outputs in dialysate from rat striatum and frontal cortex." Brain Res 551(1-2);64-71. PMID: 1680529
Milstien89: Milstien S, Kaufman S (1989). "The biosynthesis of tetrahydrobiopterin in rat brain. Purification and characterization of 6-pyruvoyl tetrahydropterin (2'-oxo)reductase." J Biol Chem 264(14);8066-73. PMID: 2656673
Schallreuter94: Schallreuter KU, Wood JM, Pittelkow MR, Gutlich M, Lemke KR, Rodl W, Swanson NN, Hitzemann K, Ziegler I (1994). "Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin." Science 263(5152);1444-6. PMID: 8128228
Tanaka89a: Tanaka K, Kaufman S, Milstien S (1989). "Tetrahydrobiopterin, the cofactor for aromatic amino acid hydroxylases, is synthesized by and regulates proliferation of erythroid cells." Proc Natl Acad Sci U S A 86(15);5864-7. PMID: 2762302
Wang11e: Wang H, Yang B, Hao G, Feng Y, Chen H, Feng L, Zhao J, Zhang H, Chen YQ, Wang L, Chen W (2011). "Biochemical characterization of the tetrahydrobiopterin synthesis pathway in the oleaginous fungus Mortierella alpina." Microbiology 157(Pt 11);3059-70. PMID: 21852350
Ashida93: Ashida A, Hatakeyama K, Kagamiyama H (1993). "cDNA cloning, expression in Escherichia coli and purification of human 6-pyruvoyl-tetrahydropterin synthase." Biochem Biophys Res Commun 195(3);1386-93. PMID: 8216273
Auerbach00: Auerbach G, Herrmann A, Bracher A, Bader G, Gutlich M, Fischer M, Neukamm M, Garrido-Franco M, Richardson J, Nar H, Huber R, Bacher A (2000). "Zinc plays a key role in human and bacterial GTP cyclohydrolase I." Proc Natl Acad Sci U S A 97(25);13567-72. PMID: 11087827
Auerbach97: Auerbach G, Herrmann A, Gutlich M, Fischer M, Jacob U, Bacher A, Huber R (1997). "The 1.25 A crystal structure of sepiapterin reductase reveals its binding mode to pterins and brain neurotransmitters." EMBO J 16(24);7219-30. PMID: 9405351
Babitzke92: Babitzke P, Gollnick P, Yanofsky C (1992). "The mtrAB operon of Bacillus subtilis encodes GTP cyclohydrolase I (MtrA), an enzyme involved in folic acid biosynthesis, and MtrB, a regulator of tryptophan biosynthesis." J Bacteriol 174(7);2059-64. PMID: 1551827
Bailey78: Bailey, S. W., Ayling, J. E. (1978). "Separation and properties of the 6-diastereoisomers of l-erythro-tetrahydrobiopterin and their reactivities with phenylalanine hydroxylase." J. Biol. Chem. 253:1598-1605.
Basset02: Basset G, Quinlivan EP, Ziemak MJ, Diaz De La Garza R, Fischer M, Schiffmann S, Bacher A, Gregory JF, Hanson AD (2002). "Folate synthesis in plants: the first step of the pterin branch is mediated by a unique bimodular GTP cyclohydrolase I." Proc Natl Acad Sci U S A 99(19);12489-94. PMID: 12221287
Burg68: Burg AW, Brown GM (1968). "The biosynthesis of folic acid. 8. Purification and properties of the enzyme that catalyzes the production of formate from carbon atom 8 of guanosine triphosphate." J Biol Chem 1968;243(9);2349-58. PMID: 4296838
Burgisser94: Burgisser DM, Thony B, Redweik U, Hunziker P, Heizmann CW, Blau N (1994). "Expression and characterization of recombinant human and rat liver 6-pyruvoyl tetrahydropterin synthase. Modified cysteine residues inhibit the enzyme activity." Eur J Biochem 219(1-2);497-502. PMID: 8307017
Burgisser95: Burgisser DM, Thony B, Redweik U, Hess D, Heizmann CW, Huber R, Nar H (1995). "6-Pyruvoyl tetrahydropterin synthase, an enzyme with a novel type of active site involving both zinc binding and an intersubunit catalytic triad motif; site-directed mutagenesis of the proposed active center, characterization of the metal binding site and modelling of substrate binding." J Mol Biol 253(2);358-69. PMID: 7563095
El06: El Yacoubi B, Bonnett S, Anderson JN, Swairjo MA, Iwata-Reuyl D, de Crecy-Lagard V (2006). "Discovery of a new prokaryotic type I GTP cyclohydrolase family." J Biol Chem 281(49);37586-93. PMID: 17032654
Gutlich94: Gutlich M, Jaeger E, Rucknagel KP, Werner T, Rodl W, Ziegler I, Bacher A (1994). "Human GTP cyclohydrolase I: only one out of three cDNA isoforms gives rise to the active enzyme." Biochem J 302 ( Pt 1);215-21. PMID: 8068008
Ichinose91: Ichinose H, Katoh S, Sueoka T, Titani K, Fujita K, Nagatsu T (1991). "Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis." Biochem Biophys Res Commun 179(1);183-9. PMID: 1883349
Nar94: Nar H, Huber R, Heizmann CW, Thony B, Burgisser D (1994). "Three-dimensional structure of 6-pyruvoyl tetrahydropterin synthase, an enzyme involved in tetrahydrobiopterin biosynthesis." EMBO J 13(6);1255-62. PMID: 8137809
Nar95a: Nar H, Huber R, Auerbach G, Fischer M, Hosl C, Ritz H, Bracher A, Meining W, Eberhardt S, Bacher A (1995). "Active site topology and reaction mechanism of GTP cyclohydrolase I." Proc Natl Acad Sci U S A 92(26);12120-5. PMID: 8618856
Park90: Park YS, Kim JH, Jacobson KB, Yim JJ (1990). "Purification and characterization of 6-pyruvoyl-tetrahydropterin synthase from Drosophila melanogaster." Biochim Biophys Acta 1038(2);186-94. PMID: 2110003
Schoedon89: Schoedon G, Redweik U, Curtius HC (1989). "Purification of GTP cyclohydrolase I from human liver and production of specific monoclonal antibodies." Eur J Biochem 178(3);627-34. PMID: 2463916
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