1.6

• Citric acid cycle


  Series of biochemical reactions in which the acetyl portion of acetyl CoA is oxidized to carbon dioxide and the reduced coenzymes FADH2 and NADH are produced
• Krebs cycle


  Another name for the citric acid cycle, after its discoverer Hans Adolf Krebs
• Tricarboxylic acid cycle


  Another name for the citric acid cycle, in reference to the three carboxylate groups present in citric acid
• The first stage of biochemical energy production, digestion, is not considered part of metabolism because it is extracellular. Metabolic processes are intracellular.
• Hans Adolf Krebs (1900–1981): 'German-born British biochemist, received the 1953 Nobel Prize in medicine for establishing the relationships among the different compounds in the cycle that carries his name, the Krebs cycle.'
• Citric acid cycle


  1. Formation of citrate

  2. Formation of isocitrate

  3. Oxidation of isocitrate and formation of CO2

  4. Oxidation of α-ketoglutarate and formation of CO2

  5. Thioester bond cleavage in succinyl CoA and phosphorylation of GDP

  6. Oxidation of succinate

  7. Hydration of fumarate

  8. Oxidation of malate
• Enzymes in the citric acid cycle

  • The chemical reactions take place in the mitochondrial matrix where the needed enzymes are found, except the succinate dehydrogenase reaction that involves FAD. The enzyme that catalyzes this reaction is an integral part of the inner mitochondrial membrane.
• Citrate synthase


  Enzyme that catalyzes the condensation of acetyl CoA and oxaloacetate to form citryl CoA, and the hydrolysis of the thioester bond in citryl CoA to produce CoA-SH and citrate
• Aconitase


  Enzyme that catalyzes the isomerization of citrate to isocitrate, involving a dehydration followed by a hydration
• Isocitrate dehydrogenase


  Enzyme that catalyzes the oxidation of isocitrate to oxalosuccinate, releasing NADH and CO2
• α-Ketoglutarate dehydrogenase complex


  Aggregate of three enzymes that catalyzes the oxidation of α-ketoglutarate to succinyl CoA, releasing NADH and CO2
• Succinyl CoA synthetase


  Enzyme that removes coenzyme A from succinyl CoA by thioester bond cleavage, and uses the released energy to phosphorylate GDP to form GTP
• Four stages of biochemical energy production

  • Digestion
  • Acetyl group formation (acetyl CoA)
  • Citric acid cycle
  • Electron transport chain and oxidative phosphorylation
• The citric acid cycle is stage 3 of biochemical energy production
• CO2


  Carbon dioxide
• NADH


  Reduced form of NAD
• Succinyl CoA


  C4 species with a high-energy thioester bond
• α-Ketoglutarate


  Intermediate in the citric acid cycle
• NAD


  Oxidizing agent in the citric acid cycle
• NADH


  Reduced form of NAD, carries electrons and H to the electron transport chain
• Step 5: Thioester bond cleavage in Succinyl CoA and Phosphorylation of GDP


  1. Succinyl CoA synthetase removes coenzyme A by thioester bond cleavage

  2. Energy released is used to combine GDP and Pi to form GTP

  3. Succinyl CoA converted to succinate
• Step 3


  • Hydroxyl group of isocitrate oxidized to a ketone group
  • NAD converted to NADH
  • Carboxyl group from oxaloacetate removed as CO2
• Step 4


  • Second NAD converted to NADH
  • Second carboxyl group removed as CO2
  • Coenzyme A reacts with decarboxylation product succinate to produce succinyl CoA
• The CO2 molecules produced in Steps 3 and 4 are the CO2 molecules we exhale in the process of respiration
• All acids found in the citric acid cycle exist as carboxylate ions at cellular pH
• Thioester bond in succinyl CoA

  Strained bond, its hydrolysis releases energy which is trapped by GTP formation
• Steps 6 through 8 of the citric acid cycle

  1. Oxidation (dehydrogenation)

  2. Hydration

  3. Oxidation (dehydrogenation)
• Step 6: Oxidation of Succinate


  • Enzyme succinate dehydrogenase, oxidizing agent FAD
  • Two hydrogen atoms removed from succinate to produce fumarate, FAD reduced to FADH2
• Step 7: Hydration of Fumarate

  • Enzyme fumarase catalyzes addition of water to fumarate double bond, only L-isomer of malate produced
• Step 8: Oxidation of L-Malate to Regenerate Oxaloacetate


  • NAD reacts with malate, picking up two hydrogen atoms to form NADH+H
  • Product is oxaloacetate, which can combine with another acetyl CoA to restart the cycle
• Important features of the citric acid cycle

  • Fuel is acetyl CoA from breakdown of carbohydrates, fats, and proteins
  • Four redox reactions, NAD or FAD as oxidizing agents
  • NADH and FADH2 carry electrons and H to electron transport chain
  • Two carbon atoms enter and leave the cycle as CO2, not the same atoms
  • Four B vitamins necessary for proper functioning
• GTP


  High-energy phosphate bond, similar function to ATP
• Regulation of the citric acid cycle

  • Rate controlled by body's need for ATP

  High ATP inhibits citrate synthase, low ATP/high ADP activates it

  Similar control mechanism at isocitrate dehydrogenase step