Updated BioCyc iOS App now
available in iTunes store
Updated BioCyc iOS App now
available in iTunes store
Updated BioCyc iOS App now
available in iTunes store
Updated BioCyc iOS App now
available in iTunes store
Updated BioCyc iOS App now
available in iTunes store

MetaCyc Pathway: superpathway of tetrahydrofolate biosynthesis
Inferred from experiment

Pathway diagram: superpathway of tetrahydrofolate biosynthesis

Note: a dashed line (without arrowheads) between two compound names is meant to imply that the two names are just different instantiations of the same compound -- i.e. one may be a specific name and the other a general name, or they may both represent the same compound in different stages of a polymerization-type pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: folic acid biosynthesis, folate biosynthesis, THF biosynthesis

Superclasses: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisVitamins BiosynthesisFolate Biosynthesis

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Escherichia coli K-12 substr. MG1655, Glycine max, Lactococcus lactis, Oryza sativa, Pisum sativum, Saccharomyces cerevisiae, Solanum lycopersicum

Expected Taxonomic Range: Bacteria , Fungi, Viridiplantae

General Background

Tetrahydrofolate (vitamin B9) and its derivatives, commonly termed folates, are essential cofactors that facilitate the transfer of one-carbon units from donor molecules into important biosynthetic pathways leading to methionine, purine, and pyrimidine biosynthesis. Folates also mediate the interconversion of serine and glycine, play a role in histidine catabolism [Lucock00], and in plants are also involved in photorespiration, amino acid metabolism and chloroplastic protein biosynthesis [Hanson02] [Jabrin03].

Folates are abundant in green leaves, and folic acid was initially isolated from a large amount (four tons) of spinach leaves. The name folate is derived from the Latin folium (leaf) [Mitchell41].

Folates are modified by the addition of glutamate moieties conjugated one to another via a series of γ-glutamyl links to form an oligo-γ-glutamyl tail. The polyglutamylated forms are usually preferred by the enzymes that use folates since the turnover rate of those compounds is markedly increased [Cossins97, Scott00, Kirk94]. In addition, in eukaryotic cells the glutamylated forms of folate facilitate the retention of the vitamin within the cell and its subcellular compartments [Appling91].

The product of this pathway, tetrahydropteroyl mono-L-glutamate (tetrahydropteroylmonoglutamate, H4PteGlu1, THF), is merely the parent structure of this large family of coenzymes. Members of the family differ in the oxidation state of the pteridine ring, the character of the one-carbon substituent at the N5 and N10 positions (see folate transformations I), and the number of conjugated glutamate residues (see folate polyglutamylation).

About This Pathway

This pathway for the de novo biosynthesis of folates is found in bacteria, fungi, and plants.

Folates are tripartite molecules and are made up of a pterin, 4-aminobenzoate and L-glutamate moieties. The first two are synthesized from GTP and chorismate, respectively. The first committed step catalyzed by GTP cyclohydrolase I converts GTP into 7,8-dihydroneopterin 3'-triphosphate. The triphosphate motif is removed by a still unknown process, and the resulting 7,8-dihydroneopterin is converted to 6-hydroxymethyl-7,8-dihydropterin by dihydroneopterin aldolase (FolB). The consecutive action of the FolK, FolP, FolC, and FolA enzymes finally produces the final product, tetrahydropteroyl mono-L-glutamate [Illarionova02].

In plants the pterin moiety is formed from GTP in the cytosol, which couples to pABA (synthesized in plastids) in mitochondria followed by subsequent glutamylation and reduction steps which may take place in cytosol, mitochondria and plastids [Hanson02, Ravanel01]. The recent discovery that folylpolyglutamate synthases are present in cytosol, mitochondria and plastids with each of them encoded by a different gene in Arabidopsis thaliana [Ravanel01] points to the fact that at least parts of the pathway can be carried out independently in those compartments.

In addition to the de novo pathway, many organisms also possess a salvage pathway that is used to re-synthesize tetrahydrofolate from breakdown products of folates in the cell, such as 5 or 10-formyl-tetrahydrofolate.

About Folates In Animals

While plants and many microorganisms can synthesize folate coenzymes by the de novo synthesis pathway, vertebrates are absolutely dependent on nutritional sources, making folate a vitamin. Food folates exist mainly as N5-methyl-tetrahydrofolate (N5-methyl-H4PteGlun) and N10-formyl-tetrahydrofolate (N10-formyl-H4PteGlun) [Thien77].

Polyglutamyl folates are hydrolyzed to folylmonoglutamates by γ-glutamyl hydrolase, and metabolized within the enterocyte into 5-methyl-H4PteGlu1. This monoglutamyl folate coenzyme is the plasma form of the vitamin [Herbert62, Lucock89], and is transported to peripheral tissues where it is demethylated by the vitamin B12-dependent folylpolyglutamate γ-glutamyl hydrolase to monoglutamyl tetrahydrofolate (H4PteGlu1).

Insufficient supply of the vitamin in vertebrates leads to anemia in adults, and has been shown to cause neural tube malformation in human embryos [Feinleib01]. In addition, folate defficiency has been linked to a number of other birth defects, several types of cancer, dementia, affective disorders, Down's syndrom, and serious conditions affecting pregnancy outcome (for a review, see [Lucock00]).

Superpathways: superpathway of chorismate metabolism, superpathway of tetrahydrofolate biosynthesis and salvage

Subpathways: tetrahydrofolate biosynthesis, 6-hydroxymethyl-dihydropterin diphosphate biosynthesis I, 4-aminobenzoate biosynthesis

Unification Links: EcoCyc:PWY-6612

Created 22-Sep-2010 by Caspi R, SRI International


Appling91: Appling DR (1991). "Compartmentation of folate-mediated one-carbon metabolism in eukaryotes." FASEB J 5(12);2645-51. PMID: 1916088

Cossins97: Cossins EA, Chen L (1997). "Folates and one-carbon metabolism in plants and fungi." Phytochemistry 45(3);437-52. PMID: 9190084

Feinleib01: Feinleib M, Beresford SA, Bowman BA, Mills JL, Rader JI, Selhub J, Yetley EA (2001). "Folate fortification for the prevention of birthdefects: case study." Am J Epidemiol 154(12 Suppl);S60-9. PMID: 11744531

Hanson02: Hanson AD, Gregory JF (2002). "Synthesis and turnover of folates in plants." Curr Opin Plant Biol 5(3);244-9. PMID: 11960743

Herbert62: Herbert V, Larrabee AR, Buchanan JM (1962). "Studies on the identification of a folate compound of human serum." J Clin Invest 41;1134-8. PMID: 13906633

Illarionova02: Illarionova V, Eisenreich W, Fischer M, Haussmann C, Romisch W, Richter G, Bacher A (2002). "Biosynthesis of tetrahydrofolate. Stereochemistry of dihydroneopterin aldolase." J Biol Chem 277(32);28841-7. PMID: 12039964

Jabrin03: Jabrin S, Ravanel S, Gambonnet B, Douce R, Rebeille F (2003). "One-carbon metabolism in plants. Regulation of tetrahydrofolate synthesis during germination and seedling development." Plant Physiol 131(3);1431-9. PMID: 12644692

Kirk94: Kirk CD, Imeson HC, Zheng LL, Cossins EA (1994). "The affinity of pea cotyledon 10-formyltetrahydrofolate synthetase for polyglutamate substrates." Phytochemistry. 35(2), 291-296.

Lucock00: Lucock M (2000). "Folic acid: nutritional biochemistry, molecular biology, and role in disease processes." Mol Genet Metab 71(1-2);121-38. PMID: 11001804

Lucock89: Lucock MD, Hartley R, Smithells RW (1989). "A rapid and specific HPLC-electrochemical method for the determination of endogenous 5-methyltetrahydrofolic acid in plasma using solid phase sample preparation with internal standardization." Biomed Chromatogr 3(2);58-63. PMID: 2736319

Mitchell41: Mitchell HK, Snell EE, Williams RJ (1941). "The concentration of "folic acid"." Journal of the American Chemical Society, Vol. 63:2284. PMID: 3067148

Ravanel01: Ravanel S, Cherest H, Jabrin S, Grunwald D, Surdin-Kerjan Y, Douce R, Rebeille F (2001). "Tetrahydrofolate biosynthesis in plants: molecular and functional characterization of dihydrofolate synthetase and three isoforms of folylpolyglutamate synthetase in Arabidopsis thaliana." Proc Natl Acad Sci U S A 98(26);15360-5. PMID: 11752472

Scott00: Scott J, Rebeille F, Fletcher J (2000). "Folic acid and folates: the feasibility for nutritional enhancement in plant foods." J Sci Food Agric 80; 795-824.

Thien77: Thien KR, Blair JA, Leeming RJ, Cooke WT, Melikian V (1977). "Serum folates in man." J Clin Pathol 30(5);438-48. PMID: 405403

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

Achari97: Achari A, Somers DO, Champness JN, Bryant PK, Rosemond J, Stammers DK (1997). "Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase." Nat Struct Biol 4(6);490-7. PMID: 9187658

Adams14: Adams NE, Thiaville JJ, Proestos J, Juarez-Vazquez AL, McCoy AJ, Barona-Gomez F, Iwata-Reuyl D, de Crecy-Lagard V, Maurelli AT (2014). "Promiscuous and adaptable enzymes fill "holes" in the tetrahydrofolate pathway in Chlamydia species." MBio 5(4). PMID: 25006229

Akhtar08: Akhtar TA, McQuinn RP, Naponelli V, Gregory JF, Giovannoni JJ, Hanson AD (2008). "Tomato gamma-glutamylhydrolases: expression, characterization, and evidence for heterodimer formation." Plant Physiol 148(2);775-85. PMID: 18757550

Anderson11: Anderson DD, Quintero CM, Stover PJ (2011). "Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria." Proc Natl Acad Sci U S A 108(37);15163-8. PMID: 21876188

Anderson91: Anderson KS, Kati WM, Ye Q-Z, Liu J, Walsh CT, Benesi AJ (1991). "Isolation and structure elucidation of the 4-amino-4-deoxychorismate intermediate in the PABA enzymatic pathway." J. Am. Chem. Soc. 113, 3198-3200.

Appleman90: Appleman JR, Howell EE, Kraut J, Blakley RL (1990). "Role of aspartate 27 of dihydrofolate reductase from Escherichia coli in interconversion of active and inactive enzyme conformers and binding of NADPH." J Biol Chem 1990;265(10);5579-84. PMID: 2108144

Arai05: Arai M, Iwakura M (2005). "Probing the interactions between the folding elements early in the folding of Escherichia coli dihydrofolate reductase by systematic sequence perturbation analysis." J Mol Biol 347(2);337-53. PMID: 15740745

Arai07: Arai M, Kondrashkina E, Kayatekin C, Matthews CR, Iwakura M, Bilsel O (2007). "Microsecond Hydrophobic Collapse in the Folding of Escherichia coli Dihydrofolate Reductase, an alpha/beta-Type Protein." J Mol Biol 368(1);219-29. PMID: 17331539

Arai11: Arai M, Iwakura M, Matthews CR, Bilsel O (2011). "Microsecond subdomain folding in dihydrofolate reductase." J Mol Biol 410(2);329-42. PMID: 21554889

Arora13: Arora K, Brooks CL (2013). "Multiple intermediates, diverse conformations, and cooperative conformational changes underlie the catalytic hydride transfer reaction of dihydrofolate reductase." Top Curr Chem 337;165-87. PMID: 23420416

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

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

Baccanari75: Baccanari D, Phillips A, Smith S, Sinski D, Burchall J (1975). "Purification and properties of Escherichia coli dihydrofolate reductase." Biochemistry 1975;14(24);5267-73. PMID: 46

Baccanari82: Baccanari DP, Daluge S, King RW (1982). "Inhibition of dihydrofolate reductase: effect of reduced nicotinamide adenine dinucleotide phosphate on the selectivity and affinity of diaminobenzylpyrimidines." Biochemistry 1982;21(20);5068-75. PMID: 6814484

Ballantine94: Ballantine SP, Volpe F, Delves CJ (1994). "The hydroxymethyldihydropterin pyrophosphokinase domain of the multifunctional folic acid synthesis Fas protein of Pneumocystis carinii expressed as an independent enzyme in Escherichia coli: refolding and characterization of the recombinant enzyme." Protein Expr Purif 5(4);371-8. PMID: 7950384

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

Basset04: Basset GJ, Ravanel S, Quinlivan EP, White R, Giovannoni JJ, Rebeille F, Nichols BP, Shinozaki K, Seki M, Gregory JF, Hanson AD (2004). "Folate synthesis in plants: the last step of the p-aminobenzoate branch is catalyzed by a plastidial aminodeoxychorismate lyase." Plant J 40(4);453-61. PMID: 15500462

Basset04a: Basset GJ, Quinlivan EP, Ravanel S, Rebeille F, Nichols BP, Shinozaki K, Seki M, Adams-Phillips LC, Giovannoni JJ, Gregory JF, Hanson AD (2004). "Folate synthesis in plants: the p-aminobenzoate branch is initiated by a bifunctional PabA-PabB protein that is targeted to plastids." Proc Natl Acad Sci U S A 101(6);1496-501. PMID: 14745019

Batruch10: Batruch I, Javasky E, Brown ED, Organ MG, Johnson PE (2010). "Thermodynamic and NMR analysis of inhibitor binding to dihydrofolate reductase." Bioorg Med Chem 18(24);8485-92. PMID: 21084197

Bauer04: Bauer S, Schott AK, Illarionova V, Bacher A, Huber R, Fischer M (2004). "Biosynthesis of tetrahydrofolate in plants: crystal structure of 7,8-dihydroneopterin aldolase from Arabidopsis thaliana reveals a novel aldolase class." J Mol Biol 339(4);967-79. PMID: 15165863

Showing only 20 references. To show more, press the button "Show all references".

Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by Pathway Tools version 19.5 (software by SRI International) on Sun May 1, 2016, biocyc14.