Regulation of the citric acid cycle

There are four major regulatory enzymes in the citric acid cycle. These are citrate synthase (step 1), isocitrate dehydrogenase (step 3), 2-oxoglutarate dehydrogenase (step 4), and succinate dehydrogenase (step 6). 

In the first control point, citrate synthase catalyzes the condensation of acetyl-CoA with oxaloacetate to produce citrate (AG° = -32.2 kJ mol ). Although the reaction is reversible, the equilibrium lies very much in favor of citrate formation because of the hydrolysis of a bond in the intermediate compound, citroyl-CoA (Fig. 12-4). Citroyl-CoA is bound to citrate synthase, and the hydrolysis of the thioester bond, to produce citrate and coenzyme A, is an exergonic process. Citrate synthase is inhibited by its substrates (acetyl-CoA and oxaloacetate), and its activity is affected by 

The third control step in the citric acid cycle is catalyzed by 2-oxoglutarate dehydrogenase. This multienzyme complex is subject to product inhibition by both NADH and succinyl-CoA. Yet again, 

The fourth control in the cycle is at the conversion of succinate to fumarate via succinate dehydrogenase. This enzyme is inhibited by oxaloacetate, so that if for any reason oxaloacetate accumulates, the enzymes will be inhibited thus, oxaloacetate feeds back and inhibits a reaction that is required for its synthesis. This phenomenon is called negative feedback. (See Chap. 9.) 

The major regulatory sites in the citric acid cycle are shown in Fig. 12-6. 

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Regulation of the Citric Acid Cycle Depends Primarily on a Supply of Oxidized Cofactors... 

A detailed review of the regulation of the citric acid cycle. 

On the basis of these observations, suggest how succinyl-CoA regulates the activity of citrate synthase. (Hint See Fig. 6-29.) Why is succinyl-CoA an appropriate signal for regulation of the citric acid cycle How does the regulation of citrate synthase control the rate of cellular respiration in pig heart tissue ... 

Williamson, J. R., and Cooper, R. V., Regulation of the citric acid cycle in mammalian systems. FEBS Lett. 

In most tissues, where the primary role of the citric acid cycle is in energy-yielding metabohsm, respiratory control via the respiratory chain and oxidative phosphorylation regulates citric acid cycle activity (Chapter 14). Thus, activity is immediately dependent on the supply of NAD, which in turn, because of the tight couphng between oxidation and phosphorylation, is dependent on the availabihty of ADP and hence, ulti-... 

Although the individual reactions of the citric acid cycle were initially worked out in vitro, using minced muscle tissue, the pathway and its regulation have also been studied extensively in vivo. By using radioactively la-... 

The other anaplerotic reactions shown in Table 16-2 are also regulated to keep the level of intermediates high enough to support the activity of the citric acid cycle. Phosphoenolpyruvate (PEP) carboxylase, for example, is activated by the glycolytic intermediate fructose 1,6-bisphosphate, which accumulates when the citric acid cycle operates too slowly to process the pyruvate generated by glycolysis. 

Figure 17.18. 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 a-ketoglutarate dehydrogenase.

The regulation of the rate of oxidative phosphorylation by the ADP level is called respiratory control or acceptor control. The level of ADP likewise affects the rate of the citric acid cycle because of its need for NAD+ and FAD. The physiological significance of this regulatory mechanism is evident. The ADP level increases when ATP is consumed, and so oxidative phosphorylation is coupled to the utilization of ATP. Electrons do not flow from fuel molecules to O ... 

The sites of regulation in the citric acid cycle involve reactions with large, negative D G values. These sites of regulation include ... 

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