MetaCyc Reaction:

Superclasses: Reactions Classified By Conversion Type Simple Reactions Chemical Reactions
Reactions Classified By Substrate Small-Molecule Reactions

EC Number:

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

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 reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, 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 synθse, formyltetrahydropteroyldiglutamate synθse, N10-formyltetrahydropteroyldiglutamate synθse, folylpoly-γ-glutamate synthase, folylpolyglutamyl synθse, folylpoly(γ-glutamate) synthase, folylpolyglutamate synθse, folylpoly-γ-glutamate synθse-dihydrofolate synθse, 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): 38.100403 Inferred 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 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

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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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