TCA cycle

• Citric acid cycle


  Also known as Krebs cycle or tricarboxylic acid cycle, it is the final common pathway for the oxidation of fuel molecules (amino acids, fatty acids and carbohydrates)
• Acetyl CoA


  The single substrate that enters the citric acid cycle
• Citric acid cycle


  1. Acetyl moiety of acetyl-CoA reacts with oxaloacetate to form citrate

  2. Citrate is isomerized to isocitrate

  3. Isocitrate undergoes dehydrogenation to form oxalosuccinate and then α-ketoglutarate

  4. α-Ketoglutarate undergoes oxidative decarboxylation to form succinyl CoA

  5. Succinyl CoA is converted to succinate

  6. Succinate is converted to fumarate

  7. Fumarate is converted to malate

  8. Malate is converted to oxaloacetate
• Citric acid cycle


  • Provides the vast majority of energy used by aerobic cells in human beings
  • Provides intermediates for biosyntheses
• Anaplerotic reactions


  Reactions that replenish the intermediates in the TCA cycle
• Many of the intermediates drawn off for biosyntheses are replenished by the formation of oxaloacetate from pyruvate
• B vitamins essential in the citric acid cycle

  • Riboflavin (as FAD)
  • Niacin (as NAD)
  • Thiamin (as thiamin diphosphate)
  • Pantothenic acid (as part of coenzyme A)
• Beriberi


  Neurological and cardiovascular disorder caused by dietary deficiency of thiamin (vitamin B1)
• In beriberi, the levels of pyruvate and α-ketoglutarate in the blood are higher than normal
• Beriberi is also occasionally seen in alcoholics who are severely malnourished and are thus thiamine deficient
• Regulation of the citric acid cycle

  • Mediated by allosteric mediators and by covalent modification of the TCA cycle enzymes
  • Flux through the pathway is also controlled by the supply of acetyl CoA
• Regulation of the citric acid cycle

  1. Allosteric regulation at the 3 irreversible steps catalyzed by citrate synthase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase

  2. Isocitrate dehydrogenase is allosterically activated by Ca2+ and ADP, and inhibited by NADH

  3. α-Ketoglutarate dehydrogenase enzyme complex is activated by Ca2+ and inhibited by NADH and succinyl CoA
• The binding of isocitrate, NAD+, Mg2+, and ADP to isocitrate dehydrogenase is mutually cooperative
• The net reaction of the citric acid cycle is the oxidation of acetyl CoA to two molecules of CO2, water and energy
• Amphibolic nature of the TCA cycle

  The cycle functions as both a catabolic pathway (to break down acetyl CoA) and an anabolic pathway (to provide building blocks for biosynthesis)
• The function of the TCA cycle at a particular time is determined by the energy conditions of the cell