Malonate is a potent competitive inhibitor of the citric acid cycle; it is a 3-c

Question

Malonate is a potent competitive inhibitor of the citric acid cycle; it is a 3-carbon dicarboxylic acid. a. Propose a mechanism for this inhibition. Which enzyme, specifically, is inhibited by malonate?

b. In attempting to elucidate the citric acid cycle, Krebs performed 2 experiments with malonate-inhibited muscle cells. In the first he added excess citrate, and in the second he added excess fumarate; he then measured the change in succinate concentration for each experiment. What did he discover, and what was the significance of this finding?

Explanation / Answer

Malonate is structurally similar to succinate. This 3C compound can bind to the enzyme succinate dehydrogenase at it active site (due to the structural similarity with succinate) and inhibits the true substrate from binding the enzyme. As a result of this, krebs cycle is inhibited.

b.

When excess of citrate was added, there was no further change in the progress of the cycle, and the reactants remained as such. However, when excess fumarate was added, the inhibition by malonate was removed, and the citric acid cycle revived.

The significance of this finding was that Kreb proved that the pathway is a cyclic pathway, and one of the compounds produced during the pathway is required for the pathway to continue. When malonate inhibited the enzyme, this compound that is required to continue the cycle do not form. When the inhibition was removed, the compound formed and the cycle was revived.

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