Formation and interconversion of putrescine and spermidine in mammalian cells

Anthony E. Pegg, Hiroshige Hibasami, Isao Matsui, Delia R. Bethell

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Abstract

Recent findings on the control of putrescine and spermidine biosynthesis and interconversion in mammalian cells are described. 1. (a)|Ornithine decarboxylase, which is responsible for putrescine production, was also able to decarboxylase lysine but the Km for lysine was 100 times greater than the Km for ornithine rendering cadaverine production unlikely under physiological conditions. No other route to cadaverine was observed. Inactivation of ornithine decarboxylase by the suicide inhibitor, α-difluoromethylornithine, depleted SV-3T3 cells of putrescine and spermidine and prevented cell growth. Either putrescine, which was efficiently converted to spermidine, or cadaverine, which was converted to N-3-aminopropyl-cadaverine, was able to restore growth of these cells. 2. (b)|Exposure to exogeous putrescine and other diamines prevented the induction of ornithine decarboxylase activity in mouse fibroblasts. The transformed SV-3T3 cell line was less sensitive to the inhibition than the control 3T3 cells. This difference correlated with a greater rate of uptake in the serum-stimulated 3T3 cells but accumulation of the diamine from the medium could not entirely account for the difference in sensitivity of ornithine decarboxylate. Therefore, it appears that this control mechanism is in some way altered in the transformed cells permitting greater accumulation of putrescine and spermidine. 3. (c)|The rate limiting factor in the conversion of putrescine to spermidine is the supply of the tissue content of this nucleoside showed that it was present at levels of only 0.8-2.8 nmol/g. Production was regulated in liver after partial hepatectomy, in androgen stimulated ventral prostate and in cardiac hypertrophy via a change in the amount of S-adenosylmethionine decarboxylase protein and via changes in the content of putrescine which activates this enzyme. Inhibition of S-adenosylmethionine decarboxylase by 1,1′-[(methylethanediylidine)dinitrilo]-bis(3-aminoguanidine), an irreversible inactivation, prevented growth of SV-3T3 cells and led to an accumulator, or putrescine and decline in spermidine showing the essential role of this enzyme in spermidine production. Addition to spermidine reversed this growth inhibition. 4. (d)|A novel spermidine acetylase has been isolated from rat liver. This enzyme forms N1-acetylspermidine and is quite different from the previously decribed polyamine acetylase which is chromatn-bound and also acts on histones. The N1-acetylspermidine synthase was induced in rat liver by treatment with the hepatotoins, carbon tetrachloride or thioacetamide, and to a smaller extent by partial hepatectomy and treatment with growth hormone. This enzyme appears to play an essential role in the conversion of spermidine to putrescine indicating that the physiological substrate for polyamine oxidase under these conditions is N1-acetylspermidine. After treatment with carbon tetrachloride, there was a 40-fold rise in hepatic putrescine levels within six hours. The rise was not prevented when increased ornithine decarboxylase was completely inhibited by the presence of α-difluoromethylornithine. These results emphasize that putrescine accumulation can be achieved either via ornithine decarboxylase or via degradation of psermidine according to the circumstances.

Original languageEnglish (US)
Pages (from-to)427-451
Number of pages25
JournalAdvances in enzyme regulation
Volume19
Issue numberC
DOIs
Publication statusPublished - 1981

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Cancer Research

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