Mammalian mutants genetically altered in CTP synthetase activity.
From wildtype mouse lymphoma cells, a clone (FURT-1A), was isolated by virtue of its resistance to 1 microM 5-fluorouracil. In comparative growth rate experiments, FURT-1A cells were also less sensitive than parental cells to the growth inhibitory effects of thymidine, deoxyguanosine, 5-fluorouridine, and arabinosylcytosine. The altered growth sensitivity of FURT-1A cells to cytotoxic nucleosides was directly related to their decreased ability to accumulate the corresponding triphosphate from exogenous nucleoside. FURT-1A cells contained elevated cytidylate nucleotide pools which prevented normal growth sensitivity and interfered with the salvage of nucleosides. Metabolic flux experiments with [3H]-uridine in situ indicated that FURT-1A cells had a 2-fold enhanced rate of conversion of UTP to CTP. Kinetic analyses indicated that the CTP synthetase activity in extracts of FURT-1A cells was refractory to inhibition by CTP. The genetic loss of normal allosteric inhibition of the CTP synthetase activity in FURT-1A cells could account for the unusual phenotypic properties of these cells.
D000818:Animals; D001692:Biological Transport; D019731:Carbon-Nitrogen Ligases; D002453:Cell Cycle; D002460:Cell Line; D003570:Cytidine Triphosphate / Q000096:biosynthesis; D003853:Deoxyribonucleosides / Q000378:metabolism; D004351:Drug Resistance; D005472:Fluorouracil / Q000633:toxicity; D008025:Ligases / Q000235:genetics* / Q000378:metabolism; D008223:Lymphoma / Q000201:enzymology; D051379:Mice; D009705:Nucleosides / Q000633:toxicity; D009711:Nucleotides / Q000378:metabolism
D003853:Deoxyribonucleosides; D009705:Nucleosides; D009711:Nucleotides; D003570:Cytidine Triphosphate; D008025:Ligases; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase; D005472:Fluorouracil