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Chapter: Biochemistry: The Citric Acid Cycle

Energetics and Control of the Citric Acid Cycle

Energetics and Control of the Citric Acid Cycle
How does the pyruvate dehydrogenase reaction control the citric acid cycle? How is control exerted within the citric acid cycle?

Energetics and Control of the Citric Acid Cycle

The reaction of pyruvate to acetyl-CoA is exergonic, as we have seen ( ∆G°' = –33.4 kJ mol–1 = –8.0 kcal mol–1). The citric acid cycle itself is also exergonic ( ∆G°' = –44.3 kJ mol–1 = –10.6 kcal mol–1), and you will be asked in Question 38 to confirm this point. The standard free-energy changes for the individual reactions are listed in Table 19.2. Of the individual reactions of the cycle, only one is strongly endergonic: the oxidation of malate to oxaloacetate ( ∆G°' = +29.2 kJ mol–1 = +7.0 kcal mol–1). This endergonic reaction is, however, coupled to one of the strongly exergonic reactions of the cycle, the condensation of acetyl-CoA and oxaloacetate to produce citrate and coenzyme A ( ∆G°' = –32.2 kJ mol–1 = –7.7 kcal mol–1). (Recall that these values for the free-energy changes refer to standard conditions. The effect of concentrations of metabolites in vivo can change matters drastically.) In addition to the energy released by the oxidation reactions, there is more release of energy to come in the electron transport chain. When the four NADH and single FADH2 produced by the pyruvate dehydrogenase complex and citric acid cycle are reoxidized by the electron transport chain, considerable quantities of ATP are produced. Controlof the citric acid cycle is exercised at three points; that is, three enzymes within thecitric acid cycle play a regulatory role (Figure 19.8). There is also control of access to the cycle via pyruvate dehydrogenase.

How does the pyruvate dehydrogenase reaction control the citric acid cycle?

The overall reaction is part of a pathway that releases energy. It is not surprising that the enzyme that initiates it is inhibited by ATP and NADH because both compounds are abundant when a cell has a good deal of energy readily available. The end products of a series of reactions inhibit the first reaction of the series, and the intermediate reactions do not take place when their products are not needed. Consistent with this picture, the pyruvate dehydrogenase (PDH) complex is activated by ADP, which is abundant when a cell needs energy. 

In mammals, the actual mechanism by which the inhibition takes place is the phosphorylation of pyruvate dehydrogenase. A phosphate group is covalently bound to the enzyme in a reaction catalyzed by the enzyme pyruvatedehydrogenase kinase. When the need arises for pyruvate dehydrogenase to beactivated, the hydrolysis of the phosphate ester linkage (dephosphorylation) is catalyzed by another enzyme, phosphoprotein phosphatase. This latter enzyme is itself activated by Ca2+. Both enzymes are associated with the mammalian pyruvate dehydrogenase complex, permitting effective control of the overall reaction from pyruvate to acetyl-CoA. The PDH kinase and PDH phosphatase are found on the same polypeptide chain. High levels of ATP activate the kinase. Pyruvate dehydrogenase is also inhibited by high levels of acetyl-CoA. This makes a great deal of metabolic sense. When fats are plentiful and are being degraded for energy, their product is acetyl-CoA. Thus, if acetyl-CoA is plentiful, there is no reason to send carbohydrates to the citric acid cycle. Pyruvate dehydrogenase is inhibited, and the acetyl-CoA for the TCA cycle comes from other sources.

How is control exerted within the citric acid cycle?

Within the citric acid cycle itself, the three control points are the reactions catalyzed by citrate synthase, isocitrate dehydrogenase, and the α-ketoglutarate dehydrogenase complex. We have already mentioned that the first reaction of the cycle is one in which regulatory control appears, as is to be expected in the first reaction of any pathway. Citrate synthase is an allosteric enzyme inhibited by ATP, NADH, succinyl-CoA, and its own product, citrate.

The second regulatory site is the isocitrate dehydrogenase reaction. In this case, ADP and NAD+ are allosteric activators of the enzyme. We have called attention to the recurring pattern in which ATP and NADH inhibit enzymes of the pathway, and ADP and NAD+ activate these enzymes.

The α-ketoglutarate dehydrogenase complex is the third regulatory site. As before, ATP and NADH are inhibitors. Succinyl-CoA is also an inhibitor of this reaction. This recurring theme in metabolism reflects the way in which a cell can adjust to an active state or to a resting state.

When a cell is metabolically active it uses ATP and NADH at a great rate, producing large amounts of ADP and NAD+ (Table 19.3). In other words, when the ATP/ADP ratio is low, the cell is using energy and needs to release more energy from stored nutrients. 

A low NADH/NAD+ ratio is also characteristic of an active metabolic state. On the other hand, a resting cell has fairly high levels of ATP and NADH. The ATP/ADP ratio and the NADH/NAD+ ratio are also high in resting cells, which do not need to maintain a high level of oxidation to produce energy.

When cells have low energy requirements (that is, when they have a high “energy charge”) with high ATP/ADP and NADH/NAD+ ratios, the presence of so much ATP and NADH serves as a signal to “shut down” the enzymes responsible for oxidative reactions. When cells have a low energy charge, char-acterized by low ATP/ADP and NADH/NAD+ ratios, the need to release more energy and to generate more ATP serves as a signal to “turn on” the oxidative enzymes. This relationship of energy requirements to enzyme activity is the basis for the overall regulatory mechanism exerted at a few key control points in metabolic pathways.


The citric acid cycle is exergonic in terms of overall free-energy changes. In addition, it produces four NADH and one FADH2 for each pyruvate that enters the cycle. Reoxidation of these electron carriers produces 25 ATP.

Four control points exist for the citric acid cycle. One, the pyruvate dehy-drogenase reaction, lies outside the cycle proper. The formation of citrate and the two oxidative decarboxylations are the other control points. ATP and NADH are inhibitors of the cycle, and ADP and NAD+ are activators.


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