Chapter 16 Citric Acid Cycle

Citric Acid Cycle Overview

  • Lehninger, Chapter 16

    • Key intermediates: oxaloacetate, acetyl-CoA, citric acid, isocitrate, a-ketoglutarate, succinyl-CoA, succinate, fumarate, malate.

Fates of Glucose

  • Glycolysis captures only a small amount of energy from glucose.

  • Utilizes cellular respiration to extract more energy.

Cellular Respiration

  • Chapter 19

    • Process in which cells consume O2 and produce CO2.

    • Provides more energy (ATP) from glucose than glycolysis through three steps:

      1. Acetyl CoA production (from pyruvate)

      2. Acetyl CoA oxidation (Citric Acid Cycle)

      3. Electron transfer and oxidative phosphorylation

Location of Reactions

  • Glycolysis occurs in the cytoplasm.

  • Citric Acid Cycle occurs in the mitochondrial matrix; however, succinate dehydrogenase is associated with the inner membrane.

  • Oxidative phosphorylation occurs in the inner membrane.

    • Energy capture from glycolysis ultimately leads to ATP formation.

Step 1: Pyruvate to Acetyl-CoA

  • Net Reaction: Irreversible oxidative decarboxylation of pyruvate removes CO2.

  • Nutritional Deficiencies: Essential vitamins involved (B1, B2, B3, B5).

  • Thioester bonds provide high-energy storage.

Advantages of Multienzyme Complexes

  • Facilitate short distances between catalytic sites for substrate channeling.

  • Minimize side-reactions and regulate activity effectively.

Five Steps of Pyruvate Decarboxylation

  1. Decarboxylation of pyruvate (release CO2).

  2. Binding of the resulting 2-C molecule to TPP.

  3. Oxidation of the 2-C to create an acetyl group.

  4. Transfer of the acetyl group to CoA, reducing lipoic acid.

  5. Reoxidation of lipoic acid via FAD, generating NADH.

Step 2: Oxidation of Acetyl-CoA in CAC

  • Begins with citric acid formation:

    • Dehydrogenation and hydration reactions orchestrate the transition from citrate to isocitrate.

  • Intermediate transformations play a crucial role in catalytic efficiency.

Step 3: Isocitrate to a-Ketoglutarate and CO2

  • Exergonic process, regulated by ATP and NADH levels.

  • NAD(P)H formation serves as an electron carrier crucial for ATP production in later stages.

Step 4: Succinyl-CoA and CO2 Formation

  • Similar to the pyruvate dehydrogenase mechanism.

  • Regulated by product inhibition, storing energy as thioester in succinyl-CoA.

ATP Generation in CAC

  • Substrate-level phosphorylation during conversion of succinyl-CoA to succinate directly forms ATP.

  • Key point of energy capture in the cycle.

Step 6: Formation of Fumarate

  • The oxidation process converts succinate to fumarate, coupled with FAD to FADH2 conversion.

  • Involves dehydrogenation; integral to electron transport chain processes.

Step 7: Formation of Malate

  • Very stereospecific reaction resulting in L-malate from trans hydration across a double bond.

Final Step of CAC: Regeneration of Oxaloacetate

  • The cycle closes by regenerating oxaloacetate.

  • This process is endergonic, requiring low concentrations of oxaloacetate for efficiency.

Summary of Energy Transformation

  • Pathway includes glycolysis and CAC, yielding total of 30-32 ATPs from glucose oxidation.

  • Aerobic metabolism is significantly more efficient than anaerobic (30-32 ATPs vs. 5-7).

Central Role of CAC

  • Functions as an amphibolic pathway, integrating various biosynthetic and energy processes.

  • Anaplerotic reactions replenish cycle intermediates, showcasing metabolic flexibility.

Regulation of CAC

  • Highly regulated at four exergonic steps, involving:

    • Substrate availability,

    • Product concentrations,

    • Allosteric feedback,

    • Covalent modifications.

Concluding Points

  • Key regulatory elements and feedback mechanisms govern CAC efficiency and reactant flow through the cycle.