Evidence for a copper:S-(methylthio)-L-homocysteine complex as a glutamine antagonist of cytidine triphosphate synthesis in L1210 murine leukemia cells.
The mixed disulfide of methyl mercaptan and L-homocysteine, S-(methylthio)-L-homocysteine (L-SMETH), inhibits the growth of L-1210 leukemia cells in culture at micromolar concentrations. The inhibition is markedly promoted by added cupric ion, but not by ions of other metals, is stereospecific, and is competitive with glutamine. For example, at 10 microM each of L-SMETH and Cu2+, almost complete growth inhibition was observed if cells were grown in 1 mM glutamine, 50% inhibition at 2 mM glutamine, and none at 4 mM glutamine. The inhibition is also completely relieved by cytidine in noncompetitive manner, but not by guanosine or uridine, indicating that the principal damage to the cellular economy resides in the amination of UTP to CTP. This was confirmed by high performance liquid chromatography analysis of cell extracts, which showed a marked decrease in CTP with increases in the levels of UTP, GTP, and ATP. A major swelling of cells leading to lysis accompanies the inhibition and increases in DNA and protein per cell confirms this unbalanced growth. The chemical basis for this biological interaction is presented.
Rabinovitz
M
M
Laboratory of Biological Chemistry, National Cancer Institute, Bethesda, Maryland 20892.
Fisher
J M
JM
D000818:Animals; D000878:Anthranilate Synthase; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000494:pharmacology*; D003570:Cytidine Triphosphate / Q000096:biosynthesis*; D003597:Cytosine Nucleotides / Q000096:biosynthesis*; D004220:Disulfides; D005973:Glutamine / Q000037:antagonists & inhibitors*; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D007939:Leukemia L1210 / Q000378:metabolism*; D008670:Metals / Q000378:metabolism; D051379:Mice; D019884:Nitrogenous Group Transferases; D009942:Organometallic Compounds / Q000494:pharmacology*; D014166:Transferases / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003597:Cytosine Nucleotides; D004220:Disulfides; D008670:Metals; D009942:Organometallic Compounds; C057187:copper-S-(methylthio)homocysteine complex; D006710:Homocysteine; D005973:Glutamine; D003570:Cytidine Triphosphate; D003300:Copper; D014166:Transferases; D019884:Nitrogenous Group Transferases; D000878:Anthranilate Synthase; C020655:anthranilate synthase, glutamine amidotransferase subunit