Biochem Lecture 11 Citric Acid Cycle

Overview of the Citric Acid Cycle

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

  • Biochemical hub of the cell, oxidizes carbon fuels (usually acetyl CoA).

  • Serves as a source of precursors for biosynthesis.

  • Krebs was awarded the Nobel Prize in 1953 after initially facing rejection from publishing in 1937.

Stages of Cellular Respiration

  1. Glycolysis

  2. Pyruvate Processing

  3. Citric Acid Cycle

  4. Electron Transport and Oxidative Phosphorylation

Inputs and Outputs of the Citric Acid Cycle

  • Occurs in:

    • Mitochondrial matrix of eukaryotes

    • Cytoplasm of prokaryotes

  • Inputs: Acetyl CoA, NAD+, FAD, ADP, Pi

  • Outputs: CO2, NADH, FADH2, ATP

Key Processes of the Citric Acid Cycle

  • Oxidation of Acetyl CoA:

    • Acetyl CoA is oxidized to CO2, generating high-energy electrons captured as NADH and FADH2.

    • Provides precursors for various biosynthetic pathways.

Stages of the Citric Acid Cycle

Stage 1: Decarboxylation

  • First Action: Formation of citrate from acetyl CoA and oxaloacetate by Citrate Synthase.

  • Aconitase: Converts citrate to isocitrate.

  • Isocitrate Dehydrogenase: Catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, producing NADH and CO2.

  • α-Ketoglutarate Dehydrogenase Complex: Converts α-ketoglutarate to succinyl CoA, producing NADH and CO2.

  • Succinyl CoA Synthetase: Cleaves succinyl CoA to produce ATP (substrate-level phosphorylation).

Stage 2: Regeneration of Oxaloacetate

  • Succinate Dehydrogenase: Converts succinate to fumarate, producing FADH2.

  • Fumarase: Converts fumarate to malate.

  • Malate Dehydrogenase: Converts malate back to oxaloacetate, producing NADH.

  • Oxaloacetate can re-enter the cycle by condensing with another acetyl CoA.

Regulation of the Citric Acid Cycle

  • Regulated by concentrations of ATP and NADH.

  • Key enzymes for regulation include:

    • Isocitrate Dehydrogenase

    • α-Ketoglutarate Dehydrogenase

Importance of Biosynthetic Precursors

  • Many intermediates in the citric acid cycle serve as precursors for other biomolecules.

  • Pyruvate carboxylase can replenish the citric acid cycle, particularly during increased exercise.

Questions to Consider

  1. What effects do inhibitors like malonate have on the cycle?

  2. Identify coenzymes required for oxidative decarboxylation of α-ketoglutarate: TPP, Lipoamide, NAD+, FAD, CoA.

  3. Are the carbons entering and exiting the cycle identical? Explain.

  • The carbons that leave as CO2 are from the oxaloacetate, not the acetyl CoA; but eventually, carbons will turn over.

Summary of Net Reaction

  • Generates 2.5 ATP from NADH and 1.5 ATP from FADH2 during oxidative phosphorylation in the electron transport chain.

  • Produces high-transfer-potential electrons and carbon dioxide, critical for cellular respiration and energy production.