Roles of folylpoly-gamma-glutamate synthetase in therapeutics with tetrahydrofolate antimetabolites: an overview.
Folylpoly-gamma-glutamate synthetase (FPGS) catalyzes the addition of several equivalents of glutamic acid to the gamma-carboxyl group in the side chain of folate cofactors and analogs. Folylpoly-gamma-glutamate synthetase has three functions in folate homeostasis in mammals: polyglutamation prevents efflux of folate cofactors from the cell, it increases the binding of folate cofactors to some of the enzymes of folate interconversion and biosynthesis, and it appears to allow the accumulation of folates in the mitochondria that are required for glycine synthesis. The efficient substrate activity of the newer generations of tetrahydrofolate analogs results in levels of intracellular accumulation of cytotoxic drug in any cell expressing FPGS in which the enzyme activity is not suppressed by feedback, and the binding of folate inhibitors of thymidylate synthase and glycinamide ribonucleotide formyltransferase is substantially increased by polyglutamation. Resistance to these drugs appears to be most frequently due to mutations that change the level of polyglutamation of parent compound, a clear indication of the centrality of the process to the cytotoxicity of these drugs. Folylpoly-gamma-glutamate synthetase is widely expressed in human tumors and is tightly linked either to proliferation or to a lack of differentiation. The cytotoxicity of both thymidylate synthase and purine inhibitors requires continued inhibition of target for greater than one generation time, so that the integrative function of FPGS adds considerably to the efficiency of folate antimetabolites.
Moran
R G
RG
Massey Cancer Center, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0230, USA.
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013763:Tetrahydrofolates / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates; C030371:5,6,7,8-tetrahydrofolic acid; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase