Inhibitors of polyamine biosynthesis. 9. Effects of S-adenosyl-L-methionine analogs on mammalian aminopropyltransferases in vitro and polyamine biosynthesis in transformed lymphocytes

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Abstract
Seven analogs of S-adenosyl-L-methionine were studied as inhibitors or substrates for mammalian spermidine and spermine synthases. 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-adenoxyl-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 .apprx. 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. The effects of 5 on transformed lymphocytes are complex and may not be solely due to the inhibition of polyamine biosynthesis by this compound.

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