Effects of certain 5'-substituted adenosines on polyamine synthesis: selective inhibitors of spermine synthase

Abstract

A number of nucleosides related to S-adenosylmethionine were tested for their inhibitory action on three enzymes involved in the biosynthesis of polyamines. The particular objective of the experiments was to determine whether any of the compounds could be used as selective inhibitors of the synthesis of spermine by spermine synthase. None of the nucleosides examined were potent inhibitors of S-adenosylmethionine decarboxylase. 5'-[(3-Aminopropyl)amino]-5'-deoxyadenosine dihydrochloride was quite a strong inhibitor of spermidine synthase (I50 of 7 microM) but was more than an order of magnitude less active than S-adenosyl-1,8-diamino-3-thiooctane, which is a mechanism-based inhibitor of this enzyme. 5'-[(3-Aminopropyl)amino]-5'-deoxyadenosine also inhibited spermine synthase with an I50 of 17 microM, but more selective inhibition of spermine synthase was produced by 9-[6(RS),8-diamino-5,6,7,8-tetradeoxy-beta-D-ribo-octofuranosyl]-9 H-purin-6- amine (I50 of 12 microM) and by dimethyl(5'-adenosyl)sulfonium perchlorate (I50 of 8 microM) since these compounds were much less active against spermidine synthase. Both 9-[6(RS),8-diamino-5,6,7,8-tetradeoxy-beta-D-ribo-octofuranosyl]-9 H-purin-6- amine and dimethyl(5'-adenosyl)sulfonium perchlorate were able to reduce the synthesis of spermine in SV-3T3 cells, but there was a compensatory increase in the concentration of spermidine, and there was no effect on cell growth. These results and those from experiments in which these spermine synthesis inhibitors were combined with inhibitors of spermidine synthase and ornithine decarboxylase indicated that the cells compensated for the inhibition of the aminopropyltransferases by increasing the production of decarboxylated S-adenosylmethionine and putrescine.(ABSTRACT TRUNCATED AT 250 WORDS)