EC - Tetrahydrofolate synthase

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IntEnz Enzyme Nomenclature


Accepted name:
tetrahydrofolate synthase
Other names:
N10-formyltetrahydropteroyldiglutamate synthetase
folate polyglutamate synthetase
folylpoly(γ-glutamate) synthase
folylpoly-γ-glutamate synthase
folylpoly-γ-glutamate synthetase-dihydrofolate synthetase
folylpolyglutamate synthase
folylpolyglutamate synthetase
folylpolyglutamyl synthetase
formyltetrahydropteroyldiglutamate synthetase
tetrahydrofolyl-[γ-Glu]n:L-glutamate γ-ligase (ADP-forming)
tetrahydrofolylpolyglutamate synthase
tetrahydrofolate:L-glutamate γ-ligase (ADP-forming)
Systematic name:
tetrahydropteroyl-[γ-polyglutamate]:L-glutamate γ-ligase (ADP-forming)



In some bacteria, a single protein catalyses both this activity and that of EC, dihydrofolate synthase [3], 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 [4]. In Arabidopsis thaliana, 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 [4]. 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 [5]). 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.

Links to other databases

Enzymes and pathways: NC-IUBMB , BRENDA , DIAGRAM , ExplorEnz , ENZYME@ExPASy , KEGG , MetaCyc , UniPathway
Protein domains and families: PROSITE:PDOC00773
Structural data: CSA , EC2PDB
Gene Ontology: GO:0004326
CAS Registry Number: 63363-84-8
UniProtKB/Swiss-Prot: (46) [show] [UniProt]


  1. Cichowicz, D., Foo, S.K. and Shane, B.
    Folylpoly-γ-glutamate synthesis by bacteria and mammalian cells.
    Mol. Cell. Biochem. 39 : 209-228 (1981). [PMID: 6458762]
  2. McGuire, J.J. and Bertino, J.R.
    Enzymatic synthesis and function of folylpolyglutamates.
    Mol. Cell. Biochem. 38 : 19-48 (1981). [PMID: 7027025]
  3. Bognar, A.L., Osborne, C., Shane, B., Singer, S.C. and Ferone, R.
    Folylpoly-γ-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. 260 : 5625-5630 (1985). [PMID: 2985605]
  4. Ravanel, S., Cherest, H., Jabrin, S., Grunwald, D., Surdin-Kerjan, Y., Douce, R. and Rébeillé, F.
    Tetrahydrofolate biosynthesis in plants: molecular and functional characterization of dihydrofolate synthetase and three isoforms of folylpolyglutamate synthetase in Arabidopsis thaliana.
    Proc. Natl. Acad. Sci. USA 98 : 15360-15365 (2001). [PMID: 11752472]
  5. Cossins, E.A. and Chen, L.
    Folates and one-carbon metabolism in plants and fungi.
    Phytochemistry 45 : 437-452 (1997). [PMID: 9190084]
  6. Cherest, H., Thomas, D. and Surdin-Kerjan, Y.
    Polyglutamylation of folate coenzymes is necessary for methionine biosynthesis and maintenance of intact mitochondrial genome in Saccharomyces cerevisiae.
    J. Biol. Chem. 275 : 14056-14063 (2000). [PMID: 10799479]

[EC created 1984, modified 2005]