Effects of S-Adenosyl-1,8-diamino-3-thiooctane on Polyamine Metabolism

Anthony Pegg, Kuo Chang Tang, James K. Coward

Research output: Contribution to journalArticle

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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-l,8-diamino-3-thiooctane at concentrations of 50 µM or greater. Such inhibition was reversed by the addition of spermidine but not by putrescine. When SV-3T3 cells were exposed to 5 mM α-(difluoromethyl)ornithine and 50 µM S-adenosyl-1,8-diamino-3-thiooctane, the content of all poly-amines was reduced. Putrescine and spermidine declined by more than 90% and spermine by 80%. Such cells grew very slowly unless spermidine was added.

Original languageEnglish (US)
Pages (from-to)5082-5089
Number of pages8
JournalBiochemistry
Volume21
Issue number20
DOIs
StatePublished - Jan 1 1982

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Spermidine
Polyamines
Metabolism
Spermidine Synthase
Putrescine
Spermine
Adenosylmethionine Decarboxylase
3T3 Cells
Spermine Synthase
Cells
Ornithine
Enzyme Inhibitors
Fibroblasts
Amines
S-adenosyl-3-thio-1,8-diaminooctane
Rats
Hepatocellular Carcinoma
Enzymes
Growth
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Pegg, Anthony ; Tang, Kuo Chang ; Coward, James K. / Effects of S-Adenosyl-1,8-diamino-3-thiooctane on Polyamine Metabolism. In: Biochemistry. 1982 ; Vol. 21, No. 20. pp. 5082-5089.
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Effects of S-Adenosyl-1,8-diamino-3-thiooctane on Polyamine Metabolism. / Pegg, Anthony; Tang, Kuo Chang; Coward, James K.

In: Biochemistry, Vol. 21, No. 20, 01.01.1982, p. 5082-5089.

Research output: Contribution to journalArticle

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N2 - 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-l,8-diamino-3-thiooctane at concentrations of 50 µM or greater. Such inhibition was reversed by the addition of spermidine but not by putrescine. When SV-3T3 cells were exposed to 5 mM α-(difluoromethyl)ornithine and 50 µM S-adenosyl-1,8-diamino-3-thiooctane, the content of all poly-amines was reduced. Putrescine and spermidine declined by more than 90% and spermine by 80%. Such cells grew very slowly unless spermidine was added.

AB - 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-l,8-diamino-3-thiooctane at concentrations of 50 µM or greater. Such inhibition was reversed by the addition of spermidine but not by putrescine. When SV-3T3 cells were exposed to 5 mM α-(difluoromethyl)ornithine and 50 µM S-adenosyl-1,8-diamino-3-thiooctane, the content of all poly-amines was reduced. Putrescine and spermidine declined by more than 90% and spermine by 80%. Such cells grew very slowly unless spermidine was added.

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