The Effect of Malonate on Tissue Respiration*

Malonate has long been regarded as a specific inhibitor for succinic dehydrogenase. The original evidence was obtained in Thunberg experiments with resting bacterial cultures (1, 2), and similar results were later obtained manometrically with brain and muscle tissue (3). The apparent specificity of this inhibition has led workers to use respiration experiments with malonate as a basis for theories of hydrogen transport (4, 5) and of carbohydrate breakdown-the “citric acid cycle” of Krebs and Johnson (6)inasmuch as malonate inhibits the respiration of intact tissue as well as of enzyme preparations. However, analytical data of Weil-Malherbe (7) suggest that malonate may not act specifically on succinic dehydrogenase in intact tissue, even though its action on purified enzyme systems be highly specific. Moreover Das (8) and Szent-GyCrgyi (9) have pointed out that fumarate and succinate differ quantitatively rather than qualitatively in their action on malonate-poisoned enzyme systems, and preliminary data of our own also seemed to indicate that malonate might not be a specific inhibitor (10). The experimental basis for the citric acid cycle has therefore been reexamined by a study of the respiration of the various component acids in the presence of malonate.