Studies on succinate dehydrogenase. Effect of monoethyl oxaloacetate, acetylene dicarboxylate, and thyroxine.

Our current studies on enzymatic mechanism and control have included consideration of the action of various types of inhibitors for the enzyme, succinate dehydrogenase (1). Interest in the succinate system stems from (a) its key role in cellular aerobic processes; and (b) the possibilities of investigation of mechanism and the action of inhibitors, partly from the point of view of an earlier investigation with the glutamate dehydrogenases (2, 3). A recent investigation (4), demonstrating that purified, soluble succinate dehydrogenases may readily be prepared from the mitochondria of various tissues, made such a study particularly timely. This investigation has disclosed the conditions under which several agents, including salicylate ion and thyroxine, exhibit noncompetitive inhibitory action with respect to the succinate system. Acetylene dicarboxylate has been found to be a characteristic competitive inhibitor. Consideration of the structural relationships among several dianionic agents, including acetylene dicarboxylate, and the well established competitors, oxaloacetate and fumarate, has suggested that the reversible binding specifically of oxaloacetate to the dehydrogenase might involve the fl-carboxylate anion together with the cis-enolate ion of the former compound. This would be alternative to the concept of possible binding by the two carboxylate anions of the ketonic tautomer of oxaloacetate, approaching the enzyme in a configuration resembling the fumarate ion. Interesting evidence bearing on such an assumption is found in the strictly competitive action now observed for the dianion, CzH50(CO) . C(O-) =CH . COO-, derived from the salt of a monoester of oxaloacetic acid in which the carboxyl anion adjacent to the ketonic carbon atom is eliminated for potential binding. This study also revealed, in the soluble, somewhat purified hog heart succinate dehydrogenase preparation, the presence of Dmalate oxidase, as well as L-malate dehydrogenase and fumarase.