Inhibitors of polyamine biosynthesis. 9. Effects of S-adenosyl-L-methionine analogues on mammalian aminopropyltransferases in vitro and polyamine biosynthesis in transformed lymphocytes.
Seven analogues of S-adenosyl-L-methionine were studied as inhibitors or substrates for mammalian spermidine and spermine synthases. One of these, S-(5'-deoxy-5'-adenosyl)-(+/-)-1-methyl-3-(methylthio)propylamine (5), showed a unique spectrum of activities on the polyamine biosynthesis enzymes. It was an inhibitor of S-adenosyl-L-methionine decarboxylase from rat liver and spermine synthase from bovine brain and rat ventral prostate. This compound was a substrate for the spermidine synthases from bovine brain and rat ventral prostate but not a substrate for the spermine synthases from these same sources. At concentrations of 0.2 mM and higher, compound 5 blocked the increases in polyamine levels and in [3H]thymidine incorporation induced by concanavalin A in cultured mouse lymphocytes. At approximately a 0.5 mM concentration of 5, the cellular polyamine levels and the rate of thymidine incorporation were similar to those of the unstimulated lymphocytes. Lower concentrations of 5 (0.02-0.1 mM) produced a dose-dependent increase in thymidine incorporation. A dose-dependent decrease in the cellular polyamine levels was observed in the range of 0.05-0.5 mM of the inhibitor. These results suggest that the effects of 5 on transformed lymphocytes are complex and may not be solely due to the inhibition of polyamine biosynthesis by this compound.
D000818:Animals; D001921:Brain / Q000201:enzymology; D002478:Cells, Cultured; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D051379:Mice; D011073:Polyamines / Q000096:biosynthesis*; D011467:Prostate / Q000201:enzymology; D012436:S-Adenosylmethionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011436:Spermidine Synthase / Q000037:antagonists & inhibitors*; D013097:Spermine Synthase / Q000037:antagonists & inhibitors; D014166:Transferases / Q000037:antagonists & inhibitors*
D011073:Polyamines; D012436:S-Adenosylmethionine; D014166:Transferases; D011436:Spermidine Synthase; D013097:Spermine Synthase