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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. 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 cytosol.
The cycle starts with the condensation of oxaloacetate (C4) and acetyl CoA (C2) 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 inorthophosphate to yield succinate, and a high phosphoryl transfer potential compound in the form of GTP 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 a compound having a high phosphoryl transfer potential is directly formed in the citric acid cycle. Hence, a total of 10 molecules of compounds having high phosphoryl transfer potential are generated for each two-carbon fragment that is completely oxidized to H2O and CO2.
The citric acid cycle operates only under aerobic conditions because it requires a supply of NAD+ and FAD. 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. The 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. 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.
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.
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.
citric acid (tricarboxylic acid, TCA; Krebs) cycle
oxidative phosphorylation
acetyl CoA
pyruvate dehydrogenase complex
flavoprotein
citrate synthase
iron-sulfur (nonheme iron) protein
isocitrate dehydrogenase
α-ketoglutarate dehydrogenase
metabolon
anaplerotic reaction
beriberi
glyoxylate cycle
isocitrate lyase
malate synthase
glyoxysome