Structure-function correlations of polyamine analog-induced increases in spermidine/spermine acetyltransferase activity

Abstract

The cytosolic enzyme, spermidine/spermine acetyltransferase (SSAT), is distinguished by its role in polyamine interconversion and by its high inducibility in response to a variety of physiological and pharmacological stimuli. Among a series of fifteen polyamines and polyamine analogs, the most potent inducers of SSAT activity in cultured L1210 cells were found to be N 1, N 8-bis(ethyl)spermidine (BES) and N 1, N 12-bis(ethyl)spermine (BESm). Over a 24-hr exposure at 10 μM, enzyme activity rose 13- and 16-fold with BES and BESm, respectively, compared to 2- to 3-fold with the anticancer agent, methylglyoxal bis(guanylhydrazone). The increase in enzyme activity by BESm began rapidly and continued steadily with time so that by 48 hr it increased to about twenty times control. By inhibitor studies, the increase was found to be due to elevated protein synthesis predominantly at the level of translation and to an apparent prolongation of enzyme half-life related to enzyme stabilization. Among the analogs, the structural requirements for maximum enzyme induction were found to be critically dependent on aminopropyl moieties and on the presence, size and location of the alkyl groups. By structure-function comparisons, it was deduced that the known abilities of BES and BESm to regulate ornithine and S-adenosylmethionine decarboxylase activities or to inhibit cell growth occur independently of their effects on SSAT activity in L1210 cells.