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The Citric Acid Cycle Is Controlled at Several Points

The rate of the citric acid cycle is precisely adjusted to meet an animal cell’s needs for ATP.The primary control points are the allosteric enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase


Control of the Citric Acid Cycle. The citric acid cycle is regulated primarily by the concentration of ATP and NADH. The key control points are the enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase.


Isocitrate dehydrogenase is allosterically stimulated by ADP, which enhances the enzyme’s affinity for substrates. The binding of isocitrate, NAD+, Mg2+, and ADP is mutually cooperative. In contrast, NADH inhibits iso-citrate dehydrogenase by directly displacing NAD+. ATP, too, is inhibitory. It is important to note that several steps in the cycle require NAD+ or FAD, which are abundant only when the energy charge is low.

A second control site in the citric acid cycle is α-ketoglutarate dehydrogenase. Some aspects of this enzyme’s control are like those of the pyruvate dehydrogenase complex, as might be expected from the homology of the two enzymes. α-Ketoglutarate dehydrogenase is inhibited by succinyl CoA and NADH, the products of the reaction that it catalyzes. In addition, α-ketoglutarate dehydrogenase is inhibited by a high energy charge. Thus, the rate of the cycle is reduced when the cell has a high level of ATP.

In many bacteria, the funneling of two-carbon fragments into the cycle also is controlled. The synthesis of citrate from oxaloacetate and acetyl CoA carbon units is an important control point in these organisms. ATP is an allosteric inhibitor of citrate synthase. The effect of ATP is to increase the value of KM for acetyl CoA. Thus, as the level of ATP increases, less of this enzyme is saturated with acetyl CoA and so less citrate is formed.

reference: “The Citric Acid cycle is Controlled at Several Points,” NCBI, assessed on April 10,  2013,

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