The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

Fpgs  -  folylpolyglutamyl synthetase

Mus musculus

Synonyms: AA408187, FPGS, Folylpoly-gamma-glutamate synthetase, Folylpolyglutamate synthase, mitochondrial, Tetrahydrofolate synthase, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of Fpgs

  • Both the L. casei and the E. coli FPGS mutant proteins bound methylene-tetrahydrofolate diglutamate and dihydropteroate normally [1].
  • Site-directed mutagenesis was performed on Glu143, an essential amino acid in Lactobacillus casei folylpolyglutamate synthetase (FPGS) and the structurally equivalent residue, Glu146, in Escherichia coli FPGS [1].
  • The exclusive use of one of two alternative sets of initial coding exons in different tissues underlies this phenomenon, suggesting the design of antifolates specific for activation by individual FPGS isoforms and hence tissue-selective targeting of antifolate therapy for cancer, arthritis, or psoriasis [2].
  • Folylpolyglutamyl synthetase (FPGS), partially purified from murine L1210 leukemia and Sarcoma 180 cells and the proliferative fraction of luminal epithelium from mouse small intestine (the site of limiting toxicity to folate analogues), was examined for its ability to utilize various 4-aminofolates as substrates [3].
  • These studies support the use of folic acid supplementation for cancer patients treated with antifolate therapy in order to prevent the biochemical changes in FR and FPGS associated with folate deficiency, prevent delayed toxicity to GARFT inhibitors and enhance the therapeutic potential of this class of drugs [4].

High impact information on Fpgs


Chemical compound and disease context of Fpgs

  • Four mutations were in the predicted ATP-, folate-, and/or glutamate-binding sites of FPGS, and two others were clustered in a peptide predicted to be beta sheet 5, based on the crystal structure of the Lactobacillus casei enzyme [6].

Biological context of Fpgs

  • These clones were used to localize murine Fpgs and Ak-1 to a region of this chromosome, namely 2 (cen leads to Cl) [7].
  • These variants incorporate two new alternatives (exons A1a and A1b) of exon 1 in the murine FPGS gene which are also spliced to exon 2 [8].
  • Nucleotide sequence analysis of independently isolated clones from a mouse liver cDNA library identified two additional splice variants of folylpolyglutamate synthetase (FPGS) mRNA with novel sequence at the 5' end [8].
  • Membrane transport was not a factor in drug resistance; rather, folypolyglutamate synthetase (FPGS) activity was decreased by >98% [6].
  • When sets of mutated cDNAs were co-transfected into FPGS-null cells to mimic the genotype of drug-selected resistant cells, clonal growth was restored [6].

Anatomical context of Fpgs

  • The data indicate that resistance to pemetrexed in the MTA-13 cell line was due to changes in both RFC and FPGS expression, two proteins that act in tandem to regulate polyglutamation of folates and antifolates in cells, resulting in cellular depletion of these active pemetrexed congeners [9].
  • Differing specificities for 4-aminofolate analogues of folylpolyglutamyl synthetase from tumors and proliferative intestinal epithelium of the mouse with significance for selective antitumor action [3].
  • Moreover, FPGS mRNA from the variant cells was significantly less effective in mediating formation of the FPGS peptide product in a manner correlating with FPGS activity and protein found in the cytosol of the various cell types [10].

Associations of Fpgs with chemical compounds

  • Chinese hamster ovary cells (AuxBl) deficient in FPGS, and consequently auxotrophic for glycine, adenosine, and thymidine (gat-), were employed as recipients in microcell-mediated chromosome transfer experiments [7].
  • We have solved the structure of the E143A mutant of L. casei FPGS in the presence of AMPPCP and Mg(2+) [1].
  • Our search for water-soluble quinazoline TS inhibitors that are transported into cells via the RFC, but are not substrates for FPGS, led us to the synthesis of dipeptide analogues of ICI 198583 diglutamate [11].
  • The value for Km derived with aminopterin was similar to that derived for either tumor cell FPGS [3].
  • Lower levels of FPGS activity in cell-free extract from these variants using EDX as substrate were characterized by the same relative decrease in value for Vmax with no change in apparent Km [10].

Analytical, diagnostic and therapeutic context of Fpgs

  • Molecular cloning of murine folylpoly-gamma-glutamate synthetase [12].
  • Findings with FPGS derived from L1210 cells were confirmed by high-pressure liquid chromatography analysis of product formation during the reaction with the parent compounds [3].
  • In addition, Northern blotting of poly(A)+ RNA did not reveal any difference in the size or level of FPGS mRNA among these various cell types [10].
  • Decreases in a 60-61-kDa protein as shown by immunoblotting with anti-FPGS peptide antibody were found to occur commensurately with the decrease in FPGS activity in cell extract from the variants compared with parental cells [10].


  1. Mutation of an essential glutamate residue in folylpolyglutamate synthetase and activation of the enzyme by pteroate binding. Sheng, Y., Cross, J.A., Shen, Y., Smith, C.A., Bognar, A.L. Arch. Biochem. Biophys. (2002) [Pubmed]
  2. Tissue-specific expression of functional isoforms of mouse folypoly-gamma-glutamae synthetase: a basis for targeting folate antimetabolites. Turner, F.B., Andreassi 2nd, J.L., Ferguson, J., Titus, S., Tse, A., Taylor, S.M., Moran, R.G. Cancer Res. (1999) [Pubmed]
  3. Differing specificities for 4-aminofolate analogues of folylpolyglutamyl synthetase from tumors and proliferative intestinal epithelium of the mouse with significance for selective antitumor action. Rumberger, B.G., Barrueco, J.R., Sirotnak, F.M. Cancer Res. (1990) [Pubmed]
  4. The role of dietary folate in modulation of folate receptor expression, folylpolyglutamate synthetase activity and the efficacy and toxicity of lometrexol. Mendelsohn, L.G., Gates, S.B., Habeck, L.L., Shackelford, K.A., Worzalla, J., Shih, C., Grindey, G.B. Adv. Enzyme Regul. (1996) [Pubmed]
  5. Similar differential for total polyglutamylation and cytotoxicity among various folate analogues in human and murine tumor cells in vitro. Samuels, L.L., Moccio, D.M., Sirotnak, F.M. Cancer Res. (1985) [Pubmed]
  6. Molecular analysis of murine leukemia cell lines resistant to 5, 10-dideazatetrahydrofolate identifies several amino acids critical to the function of folylpolyglutamate synthetase. Zhao, R., Titus, S., Gao, F., Moran, R.G., Goldman, I.D. J. Biol. Chem. (2000) [Pubmed]
  7. Complementation mapping in microcell hybrids: localization of Fpgs and Ak-1 on Mus musculus chromosome 2. Fournier, R.E., Moran, R.G. Somatic Cell Genet. (1983) [Pubmed]
  8. Additional organizational features of the murine folylpolyglutamate synthetase gene. Two remotely situated exons encoding an alternate 5' end and proximal open reading frame under the control of a second promoter. Roy, K., Mitsugi, K., Sirotnak, F.M. J. Biol. Chem. (1997) [Pubmed]
  9. Decreased expression of the reduced folate carrier and folypolyglutamate synthetase is the basis for acquired resistance to the pemetrexed antifolate (LY231514) in an L1210 murine leukemia cell line. Wang, Y., Zhao, R., Goldman, I.D. Biochem. Pharmacol. (2003) [Pubmed]
  10. Posttranscriptionally mediated decreases in folylpolyglutamate synthetase gene expression in some folate analogue-resistant variants of the L1210 cell. Evidence for an altered cognate mRNA in the variants affecting the rate of de novo synthesis of the enzyme. Roy, K., Egan, M.G., Sirlin, S., Sirotnak, F.M. J. Biol. Chem. (1997) [Pubmed]
  11. Gamma-linked dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8- dideazafolate as antitumour agents. Jackman, A.L., Bisset, G.M., Jodrell, D.I., Gibson, W., Kimbell, R., Bavetsias, V., Calvert, A.H., Harrap, K.R., Stephens, T.C., Smith, M.N. Adv. Exp. Med. Biol. (1993) [Pubmed]
  12. Molecular cloning of murine folylpoly-gamma-glutamate synthetase. Spinella, M.J., Brigle, K.E., GoldmanD, n.u.l.l. Biochim. Biophys. Acta (1996) [Pubmed]
WikiGenes - Universities