Effects of S-adenosyl-1,8-diamino-3-thiooctane on polyamine metabolism

Biochemistry. 1982 Sep 28;21(20):5082-9. doi: 10.1021/bi00263a036.

Abstract

Exposure of mammalian cells (transformed mouse fibroblasts or rat hepatoma cells) to S-adenosyl-1,8-diamino-3-thiooctane produced profound changes in the intracellular polyamine content. Putrescine was increased and spermidine was decreased, consistent with the inhibition of spermidine synthase by this compound, which is a potent and specific "transition-state analogue inhibitor" of the isolated enzyme in vitro. The spermine content of the cells was increased by exposure to this drug presumably since spermine synthase was able to use a greater proportion of the available decarboxylated S-adenosylmethionine when spermidine synthase was inhibited. The decarboxylated S-adenosylmethionine content rose substantially because the activity of S-adenosylmethionine decarboxylase was increased in response to the decline in spermidine. These results indicate that S-adenosyl-1,8-diamino-3-thiooctane is taken up by mammalian cells and is an effective inhibitor of spermidine synthase in vivo and that S-adenosylmethionine decarboxylase is regulated by the content of spermidine, but not of spermine. The growth of SV-3T3 cells was substantially reduced in the presence of S-adenosyl-1,8-diamino-3-thiooctane at concentrations of 50 microM or greater. Such inhibition was reversed by the addition of spermidine but not by putrescine. When SV-3T3 cells were exposed to 5 mM alpha-(difluoromethyl)ornithine and 50 microM S-adenosyl-1,8-diamino-3-thiooctane, the content of all polyamines was reduced. Putrescine and spermidine declined by more than 90% and spermine by 80%. Such cells grew very slowly unless spermidine was added.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology
  • Animals
  • Cell Transformation, Viral
  • Cells, Cultured
  • Fibroblasts / metabolism
  • Liver Neoplasms, Experimental / metabolism
  • Mice
  • Putrescine / metabolism*
  • Rats
  • Simian virus 40
  • Spermidine / metabolism*
  • Spermidine Synthase / antagonists & inhibitors
  • Spermine / metabolism*

Substances

  • Spermine
  • S-adenosyl-3-thio-1,8-diaminooctane
  • Spermidine Synthase
  • Adenosine
  • Spermidine
  • Putrescine