BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART II GENERATION AND STORAGE OF METABOLIC ENERGY

CHAPTER 13. THE CITRIC ACID CYCLE

Summary

The Citric Acid Cycle serves as the final common pathway for The oxidation of fuel molecules. It also acts as a source of building blocks for biosynthetic processes. Most fuel molecules enter the cycle in the form of acetyl-CoA. The oxidative decarboxylation of Pyruvate to yield acetyl-CoA links Glycolysis with The Citric Acid cycle. Unlike glycolysis, which takes place in the Cytosol, this reaction and all subsequent Reactions of the cycle occur within the Cell/35.html">Mitochondria. The cycle begins with the Condensation of oxaloacetate (C₄) and acetyl-CoA (C₂) to form citrate (C₆), which is then isomerized to isocitrate (C₆). Oxidative Decarboxylation of isocitrate yields α-ketoglutarate (C₅). A second molecule of СО₂ is released in the next reaction, where α-ketoglutarate undergoes oxidative decarboxylation to succinyl-CoA (C₄). The thioester bond of succinyl-CoA is cleaved in the presence of P_i to form succinate, simultaneously generating a high-energy phosphate bond in the form of GTP or ATP. Succinate is oxidized to fumarate (C₄), which is subsequently hydrated to malate (C₄). Finally, malate is oxidized, regenerating oxaloacetate (C₄). Thus, two carbon atoms enter the cycle as acetyl-CoA, and two carbon atoms leave the cycle as СО₂ through successive decarboxylation Reactions Catalyzed by

isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. In the four oxidation-reduction reactions of the cycle, three pairs of electrons are transferred to NAD⁺ and one pair to FAD. These reduced electron carriers are subsequently oxidized in the Electron Transport Chain, which is coupled to the generation of eleven ATP molecules. In addition, one high-energy phosphate bond is produced directly within the citric acid cycle. Consequently, for every two-carbon fragment that is completely oxidized to Н₂O and СО₂, twelve high-energy phosphate bonds are generated.

The citric acid cycle operates only under aerobic conditions because it requires a continuous supply of NAD⁺ and FAD. These electron carriers are regenerated when NADH and FADH₂ transfer their electrons to O₂ via The electron transport chain, a process coupled to ATP synthesis. Therefore, The rate of the citric acid cycle depends on The Cell's demand for ATP. Regulation of three Key Enzymes of the cycle is also of major importance in this regard. A high energy charge decreases The activity of citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase. Another critical regulatory checkpoint is the irreversible Formation of Acetyl-CoA from pyruvate. The activity of the pyruvate dehydrogenase complex is controlled by: 1) product inhibition, 2) feedback regulation by NUCLEOTIDES, and 3) covalent modification. These mechanisms act in concert to diminish the rate of acetyl-CoA production when the cellular energy charge is high.