Selection of Methotrexate-Resistant Lactobacillus Casei in the Presence of Folate or 5-Formyl-Tetrahydrofolate Affects the Resistance Mechanism

  • F. Mandelbaum-Shavit

Abstract

Reduced folate cofactors (H4PteGlu) are essential for the biosynthesis of purines, thymidine and some amino acids, thus the antimetabolites blocking their biochemical pathways (1) have been used as effective chemotherapeutics. Methotrexate (MTX), a classical antifolate inhibits the activity of dihydrofolate reductase (DHFR), consequently causing a depletion of cellular tetrahydrofolate cofactors, which results cessation of all the H4PteGlu-dependent processes. Intracellular retention and affinity of folates and MTX to target enzymes is determined by the activity of folylpolyglutamate synthetase (FPGS), which catalyses a MgATP-dependent attachment of glutamate residues to the glutamate of folates and the analogs (2,3). Another enzyme affecting the intracellular availability of the polyglutamylated folates is γ-glutamyl hydrolase (GH), which cleaves the linked polyglutamates (2,4). The biological effect of folates and the analogs thus strongly depends upon the activity of FPGS versus GH (4,5).

Keywords

Permeability Catalysis Barium Methotrexate Folate 

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References

  1. 1.
    Kisliuk R. L. “Folate biochemistry in relation to antifolate selectivity.” In Anticancer Drug Development Guide: Antifolate Drugs in Cancer Therapy, A. L. Jackman, ed., Humana Press Inc.,Totowa, NJ, pp. 13–36, 1999.Google Scholar
  2. 2.
    McGuire J. J. and Coward J. K. “Pteroylpolyglutamates: biosynthesis, degradation and function.” In R. L. Blakley and S.J. Benkovic, eds., Folates and Pterins: Chemistry and Biochemistry of Folates, John Wiley, New York, NY, vol. 1, pp. 135–190, 1984.Google Scholar
  3. 3.
    Shane B. Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism. Vitam Horm 45: 263–335, 1989.PubMedCrossRefGoogle Scholar
  4. 4.
    Galivan J., Ryan T.J., Chave K., Rhee M., Yao R., Yin D., Glutamyl hydrolase: pharmacological role and enzymatic characterization. Pharmacol Ther 85: 207–215, 2000.PubMedCrossRefGoogle Scholar
  5. 5.
    Cole P. D., Kamen B. A., Gorlick R., Bannerjee D., Smith A. K., Magill E., Bertino J. R. Effects of overexpression of gamma-glutamyl hydrolase on methotrexate metabolism and resistance. Cancer Res 61: 4599–4604, 2001.PubMedGoogle Scholar
  6. 6.
    Schimke R.T., Kaufman R.J., Alt F.W., Kellems R.F. Gene amplification and drug resistance in cultured murine cells. Science 202: 1051–1055, 1978.PubMedCrossRefGoogle Scholar
  7. 7.
    Flintoff W.F., Essani K. Methotrexate-resistant Chinese hamster ovary cells contain a dihydrofolate reductase with altered affinity for methotrexate. Bichemistry 19: 4321–4327, 1980.CrossRefGoogle Scholar
  8. 8.
    Ananthanarayan M., Kojima J.M., Henderson G.B. Structural and functional properties of the folate transport protein from a methotrexate-resistant subline of Lactobacillus casei. J Bacteriol 158: 202–207, 1984.Google Scholar
  9. 9.
    Mandelbaum-Shavit F. Resistance of Pediococcus cerevisiae to amethopterin as a consequence of changes in enzymatic activity and cell permeability. II. Permeability changes to amethopterin and other folates in the drug-resistant mutant. Biochim Biophys Acta 428: 674–682, 1976.PubMedCrossRefGoogle Scholar
  10. 10.
    Jansen G. “Receptor- and carrier-mediated transport systems for folates.” In Anti Cancer Drug Development Guide: Antifolate Drugs in Cancer Therapy, A. L. Jackman, ed., Humana Press Inc., Totowa, NJ, pp. 293–321, 1999.Google Scholar
  11. 11.
    D’Souza L., Warwick P.E., Freisheim J.H. Purification and properties of dihydrofolate reductase from an amethopterin-resistant strain of Streptococcus faecium. Biochemistry 11: 1528–1534, 1972.PubMedCrossRefGoogle Scholar
  12. 12.
    Gundersen L.E., Dunlap R.B., Harding N.G.L., Freisheim J.H., Otting F., Huennekens F. M. Dihydrofolate reductase from amethopterin-resistant Lactobacillus casei. Biochemistry 11: 1018–1023, 1972.PubMedCrossRefGoogle Scholar
  13. 13.
    Sirotnak F.M. Hyperproduction mutation the dihydrofolate reductase gene of Diplococcus pneumoniae: some effects on synthesis correlate with the presence of a modified enzyme form. Biochim Biophys Acta 313: 426–432. 1973.Google Scholar
  14. 15.
    Tamura T., Baggot J.E., Johnston K.E., Li Q.-J., Antony A.C. The form of folate affects the mechanism of methotrxate resistance in Enterococcus faecium Microbiology 143: 2639–2646, 1997.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • F. Mandelbaum-Shavit
    • 1
  1. 1.Department of BacteriologyHebrew University-Hadassah Medical SchoolJerusalemIsrael

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