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MetaCyc Reaction:

Superclasses: Reactions Classified By Conversion TypeSimple ReactionsChemical Reactions
Reactions Classified By SubstrateSmall-Molecule Reactions

EC Number:

Enzymes and Genes:

Arabidopsis thaliana col: folylpolyglutamate synthetase: DHFS/FPGS3
folylpolyglutamate synthetase: DHFS/FPGS2
folylpolyglutamate synthetase: DHFS/FPGS4
Corynebacterium sp.: tetrahydrofolate synthaseInferred from experiment: folC
Escherichia coli K-12 substr. MG1655: bifunctional folylpolyglutamate synthetase / dihydrofolate synthetaseInferred from experiment: folC
Homo sapiens: folylpolyglutamate synthase: FPGS
Lactobacillus casei: tetrahydrofolate synthaseInferred from experiment: folC

In Pathway: folate polyglutamylation

Note that this reaction equation differs from the official Enzyme Commission reaction equation for this EC number, which can be found here .

The direction shown, i.e. which substrates are on the left and right sides, is in accordance with the direction in which it was curated.

Mass balance status: Marked as unbalanced.

Enzyme Commission Primary Name: tetrahydrofolate synthase

Enzyme Commission Synonyms: folylpolyglutamate synthase, folate polyglutamate synthetase, formyltetrahydropteroyldiglutamate synthetase, N10-formyltetrahydropteroyldiglutamate synthetase, folylpoly-γ-glutamate synthase, folylpolyglutamyl synthetase, folylpoly(γ-glutamate) synthase, folylpolyglutamate synthetase, folylpoly-γ-glutamate synthetase-dihydrofolate synthetase, FPGS, tetrahydrofolylpolyglutamate synthase, tetrahydrofolate:L-glutamate γ-ligase (ADP-forming), tetrahydropteroyl-[γ-Glu]n:L-glutamate γ-ligase (ADP-forming)

Standard Gibbs Free Energy (ΔrG in kcal/mol): 38.100403Inferred by computational analysis [Latendresse13]

Enzyme Commission Summary:
In some bacteria, a single protein catalyses both this activity and that of EC, dihydrofolate synthase [Bognar85], the combined activity of which leads to the formation of the coenzyme polyglutamated tetrahydropteroate (H4PteGlun), i.e. various tetrahydrofolates (H4folate). In contrast, the activities are located on separate proteins in most eukaryotes studied to date [Ravanel01]. In Arabidopsis thaliana col, this enzyme is present as distinct isoforms in the mitochondria, the cytosol and the chloroplast. Each isoform is encoded by a separate gene, a situation that is unique among eukaryotes [Ravanel01]. As the affinity of folate-dependent enzymes increases markedly with the number of glutamic residues, the tetrahydropteroyl polyglutamates are the preferred coenzymes of C1 metabolism. (reviewed in [Cossins97]). The enzymes from different sources (particularly eukaryotes versus prokaryotes) have different substrate specificities with regard to one-carbon substituents and the number of glutamate residues present on the tetrahydrofolates.

Citations: [Cherest00, McGuire81, Cichowicz81]

Gene-Reaction Schematic

Gene-Reaction Schematic

Instance reactions of [tetrahydropteroyl-[γ-Glu](n) + L-glutamate + ATP → tetrahydropteroyl-[γ-Glu](n+1) + ADP + phosphate] (
i1: 10-formyl-tetrahydropteroyl-[γ-Glu](n) + L-glutamate + ATP → 10-formyl-tetrahydropteroyl-[γ-Glu](n+1) + ADP + phosphate (

i2: methylene-tetrahydropteroyl-[γ-Glu](n) + L-glutamate + ATP → methylene-tetrahydropteroyl-[γ-Glu](n+1) + ADP + phosphate (
i3: an (6S)-N5-formyl-tetrahydrofolate + L-glutamate + ATP = 5-formyl-THF-Glun+1 + ADP + phosphate (no EC#)

Relationship Links: BRENDA:EC:, ENZYME:EC:, IUBMB-ExplorEnz:EC:


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

Cherest00: Cherest H, Thomas D, Surdin-Kerjan Y (2000). "Polyglutamylation of folate coenzymes is necessary for methionine biosynthesis and maintenance of intact mitochondrial genome in Saccharomyces cerevisiae." J Biol Chem 275(19);14056-63. PMID: 10799479

Cichowicz81: Cichowicz DJ, Foo SK, Shane B (1981). "Folylpoly-gamma-glutamate synthesis by bacteria and mammalian cells." Mol Cell Biochem 39;209-28. PMID: 6458762

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

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

McGuire81: McGuire JJ, Bertino JR (1981). "Enzymatic synthesis and function of folylpolyglutamates." Mol Cell Biochem 38 Spec No(Pt 1);19-48. PMID: 7027025

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

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
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