Inhibitors of Polyamine Biosynthesis VII: Evaluation of Pyruvate Derivatives as Inhibitors of S-Adenosyl-L-methionine Decarboxylase

Abstract

The mechanism of the enzymatic decarboxylation of S-adenosyl-L-methionine catalyzed by S-adenosyl-L-methionine decarboxylase and its inhibition by methylglyoxal bis(guanylhydrazone) were investigated. The results indicate that the carbonyl group of the pyruvate cofactor does not form an azomethine bond with an amino group of the enzyme protein. The substrate and/or product forms an azomethine bond with the pyruvate cofactor, which can be reduced efficiently with sodium cyanoborohydride. Methylglyoxal bis(guanylhydrazone) appears to interfere with the formation of the enzyme-substrate complex by competing with the substrate for binding with the active enzyme site. The dimethylaminoethylhydrazone, semicarbazone, and guanylhydrazone derivatives of pyruvic acid, ethyl pyruvate, pyruvic acid amide, and pyruvyl glycineamide were synthesized. None of these compounds had significant inhibitory activity on the enzymatic decarboxylation of S-adenosyl-L-methionine by S-adenosyl-L-methionine decarboxylase from rat liver in vitro. These results indicate that the structural requirements for binding of methylglyoxal bis(guanylhydrazone) to the enzyme are strict and that structural modifications of this compound result in a dramatic loss of activity.