Citric Acid Cycle

A. Reactions of the Cycle

The eight enzymes of the citric acid cycle (Fig. 21-1) catalyze a series of well-known organic reactions that cumulatively ox- idize an acetyl group to two CO2 molecules with the concomi- tant generation of three NADHs, one FADH2, and one GTP:

1. Citrate synthase catalyzes the condensation of acetyl-CoA and oxaloacetate to yield citrate, giving the cycle its name.

2. The strategy of the cycle’s next two steps is to re- arrange citrate to a more easily oxidized isomer and then oxidize it. Aconitase isomerizes citrate, a not readily oxi- dized tertiary alcohol, to the easily oxidized secondary al- cohol isocitrate. The reaction sequence involves a dehydra- tion, producing enzyme-bound cis-aconitate, followed by a hydration, so that citrate’s hydroxyl group is, in effect, transferred to an adjacent carbon atom.

3. Isocitrate dehydrogenase oxidizes isocitrate to the 􏰅-keto acid intermediate oxalosuccinate with the coupled reduction of NAD􏰃 to NADH; oxalosuccinate is then de- carboxylated, yielding 􏰄-ketoglutarate. This is the first step in which oxidation is coupled to NADH production and also the first CO2-generating step.

4. The multienzyme complex 􏰄-ketoglutarate dehy- drogenase oxidatively decarboxylates 􏰄-ketoglutarate to succinyl-coenzyme A. The reaction involves the reduction of a second NAD􏰃 to NADH and the generation of a sec- ond molecule of CO2. At this point in the cycle, two mole- cules of CO2 have been produced, so that the net oxidation of the acetyl group is complete. Note, however, that it is not the carbon atoms of the entering acetyl-CoA that have been oxidized. 

5. Succinyl-CoA synthetase converts succinyl-coenzyme A to succinate. The free energy of the thioester bond is con- served in this reaction by the formation of “high-energy” GTP from GDP 􏰃 Pi.

6. The remaining reactions of the cycle serve to oxidize succinate back to oxaloacetate in preparation for another round of the cycle. Succinate dehydrogenase catalyzes the oxidation of succinate’s central single bond to a trans dou- ble bond, yielding fumarate with the concomitant reduc- tion of the redox coenzyme FAD to FADH2 (the molecular formulas of FAD and FADH2 and the reactions through which they are interconverted are given in Fig. 16-8).

7. Fumarase then catalyzes the hydration of fumarate’s double bond to yield malate.

8. Finally, malate dehydrogenase reforms oxaloacetate by oxidizing malate’s secondary alcohol group to the corre- sponding ketone with concomitant reduction of a third NAD􏰃 to NADH. Acetyl groups are thereby completely oxidized to CO2 with the following stoichiometry:

3NAD􏰃 􏰃 FAD 􏰃 GDP 􏰃 Pi 􏰃 acetyl-CoA ¡ 3NADH􏰃FADH2􏰃GTP􏰃CoA􏰃2CO2

The citric acid cycle functions catalytically as a consequence of its regeneration of oxaloacetate: An endless number of acetyl groups can be oxidized through the agency of a single oxaloacetate molecule.

NADH and FADH2 are vital products of the citric acid cycle. Their reoxidation by O2 through the mediation of the electron-transport chain and oxidative phosphorylation (Chapter 22) completes the breakdown of metabolic fuel in a manner that drives the synthesis of ATP. Other func- tions of the cycle are discussed in Section 21-5. 

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