Inhibition of Mammalian S-Adenosylmethionine Decarboxylase Activity by l,l’-[(Methylethanediylidene)- dinitrilo]bis(3=aminoguanidine)*

Inactivation of rat S-adenosylmethionine decarboxylase by l,l’-[(methylethanediylidene)dinitrilolbis(3-aminoguanidine) was studied both in vitro and in vivo. When incubated with the purified rat liver enzyme in the presence of putrestine this compound was a potent irreversible inhibitor. Inactivation proceeded as a first order reaction, which varied with the concentration of drug added but showed a rate saturation effect at high concentrations of the inhibitor. The rate of inactivation was slower in the presence of either the substrate, S-adenosylmethionine, or of l,l’I(methylethanediylidene)dinitriloldiguanidine, which is known to be a competitive inhibitor of the enzyme. However, neither compound altered the rate constant for inactivation at high concentrations of the inactivator. It was also found that l,l’-[(methylethanediylidene~dinitrilolbis(3-aminoguanidine) was a reversible inhibitor, competitive with the substrate S-adenosylmethionine, when tested in short assays by addition to the assay medium. A model in which the inhibitor first binds to the enzyme in a reversible manner and then inactivates it by reaction with an essential carbonyl group is discussed. Treatment of rats with this inhibitor showed that high doses (50 mg/kg, bqdy weight) produced a substantial and long lasting reduction of S-adenosylmethionine decarboxylase activity in kidney and liver and a smaller decrease in prostate and heart. Even in liver and kidney there was some detectable S-adenosylmethionine decarboxylase activity which could not be further reduced. Putrescine levels were significantly increased by treatment with the drug but polyamine levels were not much reduced in kidney and not at all in liver. It, therefore, appeared that the residual activity which amounted to less than 20% of the original was sufficient to maintain polyamine synthesis in the presence of the elevated concentrations of putrescine.