HGNC Approved Gene Symbol: FPGS
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38): 9:127,802,858-127,814,506 (from NCBI)
Folylpolyglutamate synthetase (FPGS) catalyzes the ATP-dependent formation of an amide bond between the gamma-carboxyl group of the naturally occurring folates and the amino group of glutamic acid. The addition of glutamic acid moieties to folate compounds allows their intracellular retention and concentration. As a result of its role in the retention of folate cofactors in the cell, FPGS is essential for the survival of proliferating mammalian cells (summary by Freemantle et al., 1995).
Kao and Puck (1968) isolated an auxotrophic mutant in Chinese hamster ovary cells which was designated GAT- because of its multiple requirements for glycine, adenine and thymidine for growth. Since aminopterin mimicked the effect of the mutant in CHO cells, a defect in folic acid metabolism was suspected. Taylor and Hanna (1977) demonstrated a defect in folylpolyglutamate synthetase (FPGS).
By functional complementation of an Escherichia coli folC mutant, Garrow et al. (1992) cloned a human cDNA for folylpoly(gamma-glutamate) synthetase (FPGS; tetrahydrofolate:L-glutamate gamma-ligase (ADP forming); EC 6.3.2.17). The cDNA encodes a 545-residue protein of Mr 60,128. Expression of the cDNA in E. coli resulted in elevated expression of an enzyme with characteristics of mammalian FPGS. Furthermore, expression of the cDNA in AUXB1, a mammalian cell lacking FPGS activity, overcame the cell's requirement for thymidine and purines but did not overcome the cell's glycine auxotrophy, consistent with expression of the protein in the cytosol but not in the mitochondria.
Freemantle et al. (1995) proposed that the mitochondrial and cytosolic forms of FPGS are, in fact, derived from the same gene, arising from the use of the 2 different translation initiation codons, and that the translation products differ by the presence of a 42-residue amino-terminal mitochondrial leader peptide. Taylor et al. (1995) likewise concluded that a single locus encodes FPGS-related sequences in the human genome.
Taylor et al. (1995) reported that the complete 2,256 nucleotides of FPGS cDNA for the 5-prime untranslated region, mitochondrial leader sequence, coding region, and 3-prime untranslated region are distributed on 15 exons stretching over 11.2 kb of genomic DNA.
By hybridization of human cell with GAT- CHO cells, Jones and Kao (1979) assigned a complementing gene, presumably FPGS, to human chromosome 9. By somatic cell hybridization, Jones and Kao (1984) regionalized the assignment to 9cen-q34.
Freemantle, S. J., Taylor, S. M., Krystal, G., Moran, R. G. Upstream organization of and multiple transcripts from the human folylpoly-gamma-glutamate synthetase gene. J. Biol. Chem. 270: 9579-9584, 1995. [PubMed: 7721888] [Full Text: https://doi.org/10.1074/jbc.270.16.9579]
Garrow, T. A., Admon, A., Shane, B. Expression cloning of a human cDNA encoding folylpoly(gamma-glutamate) synthetase and determination of its primary structure. Proc. Nat. Acad. Sci. 89: 9151-9155, 1992. [PubMed: 1409616] [Full Text: https://doi.org/10.1073/pnas.89.19.9151]
Jones, C., Kao, F. T. Assignment of the human gene complementing the auxotrophic marker GAT-minus to chromosome 9. (Abstract) Cytogenet. Cell Genet. 25: 168, 1979.
Jones, C., Kao, F.-T., Taylor, R. T. Chromosomal assignment of the gene for folylpolyglutamate synthetase to human chromosome 9. Cytogenet. Cell Genet. 28: 181-194, 1980. [PubMed: 6934068] [Full Text: https://doi.org/10.1159/000131529]
Jones, C., Kao, F.-T. Regional mapping of the folylpolyglutamate synthetase gene (FPGS) to 9cen-q34. (Abstract) Cytogenet. Cell Genet. 37: 499-500, 1984.
Kao, F. T., Puck, T. T. Genetics of somatic mammalian cells. VII. Induction and isolation of nutritional mutants in Chinese hamster cells. Proc. Nat. Acad. Sci. 60: 1275-1281, 1968. [PubMed: 5244736] [Full Text: https://doi.org/10.1073/pnas.60.4.1275]
Sussman, D. J., Milman, G., Shane, B. Characterization of human folylpolyglutamate synthetase expressed in Chinese hamster ovary cells. Somat. Cell Molec. Genet. 12: 531-540, 1986. [PubMed: 3466358] [Full Text: https://doi.org/10.1007/BF01671939]
Taylor, R. T., Hanna, M. L. Folate-dependent enzymes in cultured Chinese hamster cells: folylpolyglutamate synthetase and its absence in mutants auxotrophic for glycine, adenosine and thymidine. Arch. Biochem. Biophys. 181: 331-344, 1977. [PubMed: 18110] [Full Text: https://doi.org/10.1016/0003-9861(77)90512-4]
Taylor, S. M., Freemantle, S. J., Moran, R. G. Structural organization of the human folylpoly-gamma-glutamate synthetase gene: evidence for a single genomic locus. Cancer Res. 55: 6030-6034, 1995. [PubMed: 8521387]