Inhibition of succinic dehydrogenase by oxalacetate.

Although the inhibition of succinic dehydrogenase by oxalacetate is a generally accepted fact, there is a paucity of data on the subject. In 1937 Das (l), using a modified Thunberg technique, reported that the enzyme was 50 per cent inhibited by 2 X 1O-5 M oxalacetate when the succinate concentration was 0.025 M. In 1939 Potter (2) reported that the oxidation of succinate by liver and kidney homogenates was inhibited by cozymase (DPN). Keilin and Hartree (3) and Mann and Quastel (4) attributed this effect, no doubt correctly, to the formation of oxalacetate, although no data on the effect of oxalacetate were presented. The inhibitory effect of DPN upon the succinate system was later studied by Swingle, Axelrod, and Elvehjem (5) who also determined the effect of oxalacetate upon the succinic dehydrogenase system by measuring oxygen uptake. They reported that at succinate concentrations of 0.045 M oxalacetate produced 98, 65, and 22 per cent inhibition at concentrations of 50, 10, and 5 X 10e5 M. From the data given it is not possible to tell whether the inhibition was transitory, as will be shown below, or whether the experiments were of such short duration that the decreased inhibition was not revealed. Since we found that the inhibition declined with time, it is clear that the earlier experiments (1,5) cannot be accepted as quantitative measures of the inhibition by oxalacetate. They do, however, establish the fact that this substance has a remarkable affinity for the succinic enzyme; remarkable because it appears to be at least 1000 times greater than the affinity of the normal substrate for the enzyme, and because oxalacetate has been assumed to be formed in the course of succinat.e oxidation. If the physiologically formed oxalacetate were as toxic to succinate oxidation as added oxalacetate, the inhibition would have profound regulatory effects upon oxidative metabolism. Such does not seem to be the case, however, although the reasons are as yet obscure.