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.
Synonyms: folic acid biosynthesis, folate biosynthesis, THF biosynthesis
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Vitamins Biosynthesis → Folate Biosynthesis|
Some taxa known to possess this pathway include : Arabidopsis thaliana col , Escherichia coli K-12 substr. MG1655 , Glycine max , Lactococcus lactis , Pisum sativum , Saccharomyces cerevisiae , Solanum lycopersicum
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 (see pathway 6-hydroxymethyl-dihydropterin diphosphate biosynthesis I for the biosynthesis of the former). 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 salvage pathways that are 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-tetrahydropteroyl mono-L-glutamate (5-methyl-H4PteGlun) and 10-formyl-tetrahydrofolate mono-L-glutamate (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]).
Variants: 4-aminobenzoate biosynthesis , folate polyglutamylation , folate transformations I , folate transformations II , glutamate removal from folates , N10-formyl-tetrahydrofolate biosynthesis , tetrahydrofolate salvage from 5,10-methenyltetrahydrofolate
Unification Links: EcoCyc:PWY-6614
Feinleib01: Feinleib M, Beresford SA, Bowman BA, Mills JL, Rader JI, Selhub J, Yetley EA (2001). "Folate fortification for the prevention of birth defects: case study." Am J Epidemiol 154(12 Suppl);S60-9. PMID: 11744531
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
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
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
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
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
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
Arai07a: 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
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
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
Bershtein12: Bershtein S, Mu W, Wu W, Shakhnovich EI (2012). "Soluble oligomerization provides a beneficial fitness effect on destabilizing mutations." Proc Natl Acad Sci U S A 109(13);4857-62. PMID: 22411825
Bhabha11: Bhabha G, Lee J, Ekiert DC, Gam J, Wilson IA, Dyson HJ, Benkovic SJ, Wright PE (2011). "A dynamic knockout reveals that conformational fluctuations influence the chemical step of enzyme catalysis." Science 332(6026);234-8. PMID: 21474759
Bhabha11a: Bhabha G, Tuttle L, Martinez-Yamout MA, Wright PE (2011). "Identification of endogenous ligands bound to bacterially expressed human and E. coli dihydrofolate reductase by 2D NMR." FEBS Lett 585(22);3528-32. PMID: 22024482
Boehr08: Boehr DD, Dyson HJ, Wright PE (2008). "Conformational relaxation following hydride transfer plays a limiting role in dihydrofolate reductase catalysis." Biochemistry 47(35);9227-33. PMID: 18690714
Boehr10: Boehr DD, McElheny D, Dyson HJ, Wright PE (2010). "Millisecond timescale fluctuations in dihydrofolate reductase are exquisitely sensitive to the bound ligands." Proc Natl Acad Sci U S A 107(4);1373-8. PMID: 20080605
Bognar85: Bognar AL, Osborne C, Shane B, Singer SC, Ferone R (1985). "Folylpoly-gamma-glutamate synthetase-dihydrofolate synthetase. Cloning and high expression of the Escherichia coli folC gene and purification and properties of the gene product." J Biol Chem 1985;260(9);5625-30. PMID: 2985605
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