Tadao Ikeda

Dicyclohexylamine, a potent inhibitor of spermidine synthase in mammalian cells

Much effort has been made to develop specific inhibitors of polyamine synthesis which may help in elucidating the role of polyamines in cellular metabolism and in cell proliferation in particular [l-7]. Furthermore, inhibitors of polyamine synthesis may find applications as antiproliferative agents. Four enzymes are involved in the synthesis of polyamines in eukaryotic cells, i.e., ornithine decarboxylase, S-adenosylmethionine(SAM) decarboxylase and two aminopropyltransferases, one catalyzing the synthesis of spermidine, the other producing spermine [8-121. Most inhibitory used are inhibitors of the two decarboxylases, whereas several inhibitors are reported at the aminopropyltransferases [ 13-151. The relative activities of these enzymes must determine which of the polyamines accumulate in the cells. Marked differences in the spermidine to spermine ratio have been observed in comparisons of various mammalian cells [8,16] and spermidine levels are usually elevated in response to growth-promoting stimuli [8,16,17]. Here we demonstrate that partially purified spermidine synthase from rat ventral prostate was strongly inhibited by dicyclohexylamine and also by cyclohexylamine, and that administration of dicyclohexylamine caused a decrease in the concentration of spermidine but not spermine in the liver of partially hepatectomized rats. These inhibitors may be useful as experimental tools for elucidating the physiological function of the polyamines.

Inhibition of aminopropyltransferases by S-adenosylmethionine: Effect of simultaneous administration of S-adenosylmethionine and methylglyoxal bis(guanylhydrazone) on polyamine concentrations in regenerating rat liver

There has been intensive research activity into the biosynthetic pathway and the function of polyamines in the past decade (l-41. Considerable progress in elucidating the function of the poly~ines has been made by utilizing inhibitors of their biosynthesis [2,4-81. All of the inhibitors now in use act on either ornithine or ~-adenosy~et~on~e (SAM) decarboxyiases 16-91. None has been shown to produce substantial depletion of intracellular spermine. Here we demonstrate that partially purified aminopropyltr~sfera~s from rat liver were strongly inhibited by SAM and that administration of SAM in combination with methylglyoxal bis(guanylhydrazone) (MGBG) caused a decrease in the concentration not only of spermid~e, but also of sper~e in the liver and kidney of partially hepatectomized rats. This observation may be useful for understanding the regulation of polyamine synthesis in eukaryotic cells.

Increased proportion of medium chain fatty acids in nystatin-resistant yeast mutants

Fatty acid composition of phospholipids and steryl esters from four nystatin-resistant mutants ofSaccharomyces cerevisiae was compared to that from the wild strain. All the mutant strains which produce several ergosterol intermediates incorporated two-to three-fold as much medium chain fatty acids, especially 14:0 and 14:1 in phospholipids, and 12:0, 14:0 and 14:1 in steryl esters as the wild strain did. The increase in the relative amount of medium chain fatty acids in these mutants was found at all the growth temperatures and the growth phases examined, and in all the phospholipid species.