The citric acid cycle is the final common pathway for the oxidation of fuel molecules. It also serves as a source of building blocks for biosyntheses.

17.1 The Pyruvate Dehydrogenase Complex Links Glycolysis to the Citric Acid Cycle

Most fuel molecules enter the cycle as acetyl CoA. The link between glycolysis and the citric acid cycle is the oxidative decarboxylation of pyruvate to form acetyl CoA. In eukaryotes, this reaction and those of the cycle take place inside mitochondria, in contrast with glycolysis, which takes place in the cytoplasm.

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17.2 The Citric Acid Cycle Oxidizes Two-Carbon Units

The cycle starts with the condensation of oxaloacetate (C₄) and the acetyl unit (C₂) of acetyl CoA to give citrate (C₆), which is isomerized to isocitrate (C₆). Oxidative decarboxylation of this intermediate gives α-ketoglutarate (C₅). The second molecule of carbon dioxide comes off in the next reaction, in which α-ketoglutarate is oxidatively decarboxylated to succinyl CoA (C₄). The thioester bond of succinyl CoA is cleaved by orthophosphate to yield succinate, and an ATP is concomitantly generated. Succinate is oxidized to fumarate (C₄), which is then hydrated to form malate (C₄). Finally, malate is oxidized to regenerate oxaloacetate (C₄). Thus, two carbon atoms from acetyl CoA enter the cycle, and two carbon atoms leave the cycle as CO₂ in the successive decarboxylations catalyzed by isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. In the four oxidation–reduction reactions in the cycle, three pairs of electrons are transferred to NAD⁺ and one pair to FAD. These reduced electron carriers are subsequently oxidized by the electron-transport chain to generate approximately 9 molecules of ATP. In addition, 1 molecule of ATP is directly formed in the citric acid cycle. Hence, a total of 10 molecules of ATP are generated for each two-carbon fragment that is completely oxidized to H₂O and CO₂.

17.3 Entry to the Citric Acid Cycle and Metabolism Through It Are Controlled

The citric acid cycle operates only under aerobic conditions because it requires a supply of NAD⁺ and FAD. These electron acceptors are regenerated when NADH and FADH₂ transfer their electrons to O₂ through the electron-transport chain, with the concomitant production of ATP. Consequently, the rate of the citric acid cycle depends on the need for ATP. The irreversible formation of acetyl CoA from pyruvate is an important regulatory point for the entry of glucose-derived pyruvate into the citric acid cycle. The activity of the pyruvate dehydrogenase complex is stringently controlled by reversible phosphorylation. In eukaryotes, the regulation of two enzymes in the cycle also is important for control. A high energy charge diminishes the activities of isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. These mechanisms complement each other in reducing the rate of formation of acetyl CoA when the energy charge of the cell is high and when biosynthetic intermediates are abundant.

17.4 The Citric Acid Cycle Is a Source of Biosynthetic Precursors

When the cell has adequate energy available, the citric acid cycle can also provide a source of building blocks for a host of important biomolecules, such as nucleotide bases, proteins, and heme groups. This use depletes the cycle of intermediates. When the cycle again needs to metabolize fuel, anaplerotic reactions replenish the cycle intermediates.

17.5 The Glyoxylate Cycle Enables Plants and Bacteria to Grow on Acetate

The glyoxylate cycle enhances the metabolic versatility of many plants and bacteria. This cycle, which uses some of the reactions of the citric acid cycle, enables these organisms to subsist on acetate because it bypasses the two decarboxylation steps of the citric acid cycle.