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MetaCyc Pathway: tetrahydrobiopterin biosynthesis I
Traceable author statement to experimental support

Enzyme View:

Pathway diagram: tetrahydrobiopterin biosynthesis I

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: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisTetrahydrobiopterin Biosynthesis

Some taxa known to possess this pathway include : Drosophila melanogaster, Homo sapiens, Mortierella alpina, Neurospora crassa, Phycomyces blakesleeanus, Synechococcus elongatus

Expected Taxonomic Range: Bacteroidetes/Chlorobi group, Cyanobacteria, Euglenozoa, Fungi, Metazoa

General Background

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 L-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 [Tanaka89], 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, Wang11f].

About This Pathway

Tetrahydrobiopterin is formed de novo from GTP via a sequence of three enzymatic steps. The pathway involves two intermediates, 7,8-dihydroneopterin 3'-triphosphate and 6-pyruvoyl tetrahydropterin, which have been isolated, although they are rather unstable. The three enzymes of the pathway, GTP cyclohydrolase, 6-pyruvoyl tetrahydrobiopterin synthase and sepiapterin reductase, are required and sufficient. Another variant of the pathway that involves a fourth enzyme may exists in some tissues, as described in tetrahydrobiopterin biosynthesis II.

In mammals the sepiapterin reductase enzyme produces L-erythro-5,6,7,8-tetrahydrobiopterin, as described here. In the bacterium Chlorobaculum tepidum the enzyme produces L-threo-5,6,7,8-tetrahydrobiopterin (see tetrahydrobiopterin biosynthesis III) [Cho99].

Variants: tetrahydrobiopterin biosynthesis II, tetrahydrobiopterin biosynthesis III

Created 20-Sep-2007 by Caspi R, SRI International


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

Cho99: Cho SH, Na JU, Youn H, Hwang CS, Lee CH, Kang SO (1999). "Sepiapterin reductase producing L-threo-dihydrobiopterin from Chlorobium tepidum." Biochem J 340 ( Pt 2);497-503. PMID: 10333495

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

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

Tanaka89: 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

Thony00: Thony B, Auerbach G, Blau N (2000). "Tetrahydrobiopterin biosynthesis, regeneration and functions." Biochem J 347 Pt 1;1-16. PMID: 10727395

Wang11f: 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

WernerFelmayer02: Werner-Felmayer G, Golderer G, Werner ER (2002). "Tetrahydrobiopterin biosynthesis, utilization and pharmacological effects." Curr Drug Metab 3(2);159-73. PMID: 12003348

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

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

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

Bowling08: Bowling KM, Huang Z, Xu D, Ferdousy F, Funderburk CD, Karnik N, Neckameyer W, O'Donnell JM (2008). "Direct binding of GTP cyclohydrolase and tyrosine hydroxylase: regulatory interactions between key enzymes in dopamine biosynthesis." J Biol Chem 283(46);31449-59. PMID: 18801743

BRENDA14: BRENDA team (2014). Imported from BRENDA version existing on Aug 2014.

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

Choi05b: Choi YK, Jun SR, Cha EY, Park JS, Park YS (2005). "Sepiapterin reductases from Chlorobium tepidum and Chlorobium limicola catalyze the synthesis of L-threo-tetrahydrobiopterin from 6-pyruvoyltetrahydropterin." FEMS Microbiol Lett 242(1);95-9. PMID: 15621425

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

Fan76: Fan CL, Brown GM (1976). "Partial purification and properties of guanosine triphosphate cyclohydrolase from Drosophila melanogaster." Biochem Genet 14(3-4);259-70. PMID: 822834

Ferdousy11: Ferdousy F, Bodeen W, Summers K, Doherty O, Wright O, Elsisi N, Hilliard G, O'Donnell JM, Reiter LT (2011). "Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism." Neurobiol Dis 41(3);669-77. PMID: 21147225

Funderburk06: Funderburk CD, Bowling KM, Xu D, Huang Z, O'Donnell JM (2006). "A typical N-terminal extensions confer novel regulatory properties on GTP cyclohydrolase isoforms in Drosophila melanogaster." J Biol Chem 281(44);33302-12. PMID: 16966327

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

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Lee02: Lee S, Ahn C, Park E, Hwang DS, Yim J (2002). "Biochemical characterization of oligomerization of Escherichia coli GTP cyclohydrolase I." J Biochem Mol Biol 35(3);255-61. PMID: 12297008

Mackay83: Mackay WJ, O'Donnell JM (1983). "A genetic analysis of the pteridine biosynthetic enzyme, guanosine triphosphate cyclohydrolase, in Drosophila melanogaster." Genetics 105(1);35-53. PMID: 6413298

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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