Lecture 3-7: Citric Acid Cycle and Regulation of Metabolism

Citric Acid Cycle & Regulation of Metabolism

• Key Inputs:

  • Pyruvate: End product of glycolysis and enters the citric acid cycle.

  • Glucose 6-Phosphate: An important metabolite derived from glucose.

  • Acetyl CoA: A critical metabolic intermediate that enters the citric acid cycle.

Overview of the Citric Acid Cycle

• Also known as the Tricarboxylic Acid (TCA) Cycle or Krebs Cycle.

• Involves a series of step-wise oxidation reactions that produce activated carriers (NADH, FADH2, GTP).

Glycolysis and Entry/Exit Points of the Citric Acid Cycle

• Glycolysis:

  • Involves the conversion of glucose into various intermediates, including glucose 6-phosphate, fructose 6-phosphate, and ultimately pyruvate.

• Key Intermediates and Their Roles:

  • Glucose → Pyruvate

  • Pyruvate → Acetyl CoA (entry into the citric acid cycle).

  • Involvement of various amino acids and metabolites in the cycle, such as serine, alanine, aspartate.

Steps of the Citric Acid Cycle

Step 1: Citrate Synthesis

• Enzyme: Citrate Synthase

• Free Energy Change (AG°'): +0.43 kJ/mol

  • Acetyl CoA reacts with oxaloacetate, forming citrate through a hydrolysis reaction.

Step 2: Isomerization of Citrate

• Free Energy Change (AG): +0.49 kJ/mol (removal and re-addition of water)

• Enzyme: Aconitase

• Converts citrate to its isomer, isocitrate.

Step 3: Isocitrate Decarboxylation

• Enzyme: Isocitrate Dehydrogenase

• AG°: -12.66 kJ/mol

  • Isocitrate is converted to oxalosuccinate and then to alpha-ketoglutarate, releasing CO2.

Step 4: a-Ketoglutarate Decarboxylation

• Combined energy change: DG°′ = -16.37 kJ/mol

  • Involves conversion of alpha-ketoglutarate to succinyl CoA with the release of CO2.

Step 5: CoA Release from Succinyl CoA

• High-energy thioester bond between succinate and Coenzyme A.

• Provides energy for transferring a phosphate group to GDP, generating GTP.

Step 6: Succinate Oxidation

• AG°': -8.63 kJ/mol

• Enzyme: Succinate Dehydrogenase

  • Succinate is oxidized, transferring electrons to FAD, forming FADH2.

Step 7: Fumarate Hydration

• Enzyme: Fumarase

• AG: -0.21 kJ/mol

  • Water is added to fumarate to form malate.

Step 8: Malate Oxidation

• Enzyme: Malate Dehydrogenase

• **AG°' = -10.81 kJ/mol

  • Malate is oxidized to regenerate oxaloacetate, completing the cycle.

Energy Capture in the Cycle

• Energy is captured primarily in the form of NADH, GTP, and FADH2 through various reactions.

• Most reactions are either spontaneous or nearly spontaneous, allowing for efficient energy extraction.

Role of Oxygen in ATP Production

• Oxygen is essential as the final electron acceptor in oxidative phosphorylation to produce ATP from electron carriers generated in the cycle.

Gluconeogenesis and Blood Glucose Regulation

• Gluconeogenesis: Production of glucose from non-carbohydrate precursors, such as amino acids in the liver.

• Glycogen storage in liver and muscle provides readily available energy sources.

• Energy can also be stored in the form of fats for potential long-term use.

Key Concepts

• The citric acid cycle extracts energy from pyruvate and other molecules through spontaneous reactions.

• Inhibitor studies have revealed the cyclical nature of the cycle, demonstrating the significance of intermediates.

• Glucose regulation involves its conversion to glycogen and fat, ensuring energy availability in different metabolic states.