Citric Acid Cycle Notes

Chapter 19: The Citric Acid Cycle

Chapter Outline

  1. The central role of the citric acid cycle in metabolism

  2. The overall pathway of the citric acid cycle

  3. How pyruvate is converted to acetyl-CoA

  4. The individual reactions of the citric acid cycle

  5. Energetics and control of the citric acid cycle

  6. The citric acid cycle in catabolism

  7. The citric acid cycle in anabolism

  8. The link to oxygen

The Central Role of the Citric Acid Cycle

  • The evolution of aerobic metabolism allows for more energy extraction from nutrients compared to anaerobic processes.

  • Glycolysis yields 2 ATP per glucose molecule, but complete aerobic oxidation can produce 30-32 ATP.

  • Key processes in aerobic metabolism include:

    • Citric Acid Cycle (CAC): Central pathway in metabolism

    • Electron Transport Chain (ETC): Series of oxidation-reduction reactions that transfer electrons to oxygen

    • Oxidative Phosphorylation: Generates ATP using a pH gradient in mitochondria

Overview of the Citric Acid Cycle (CAC)

  • Also known as the Krebs cycle or tricarboxylic acid (TCA) cycle.

  • CAC further oxidizes carbon structures, producing high-energy carriers like NADH and FADH2.

  • Occurs within mitochondrial matrix, while glycolysis occurs in cytosol (for eukaryotes).

  • Most enzymes for CAC are located in the mitochondrial matrix.

Amphibolic Nature of CAC Intermediates

  • In aerobic organisms, CAC functions as an amphibolic pathway (catabolic and anabolic).

  • Intermediates from the citric acid cycle serve as precursors in various biosynthetic pathways.

Mitochondrial Structure

  • Mitochondria have both inner and outer membranes.

  • The mitochondrial matrix is enclosed by the inner membrane, with an intermembrane space crucial for H+ gradient and ATP synthesis.

  • Nearly all reactions of CAC take place in the matrix, while the ETC operates on the inner membrane.

  • Red blood cells lack mitochondria; thus, they can only perform glycolysis.

Reactions in Citric Acid Cycle

  • Pyruvate from glycolysis is oxidized to one CO2 molecule and one acetyl group linked to Coenzyme A (CoA).

  • Each acetyl-CoA entering the CAC produces two CO2 molecules and transfers electrons to:

    • NAD+ (reduced to NADH)

    • FAD (reduced to FADH2)

Steps of CAC

  • The cycle comprises eight steps, where:

    • One acetyl-CoA molecule enters, resulting in two CO2 molecules released.

    • Four of the eight steps are oxidation reactions.

Detailed Steps

  1. C-C Bond Formation: Acetyl-CoA condensation with oxaloacetate produces citrate, catalyzed by citrate synthase, an allosteric enzyme inhibited by NADH, ATP, and succinyl-CoA.

  2. Isomerization: Citrate is converted to isocitrate via dehydration and rehydration, enabling better substrate for oxidation.

  3. Oxidative Decarboxylation: Isocitrate loses one carbon, producing NADH and releasing CO2, catalyzed by isocitrate dehydrogenase.

  4. Final Oxidative Decarboxylation: Catalyzed by the α-ketoglutarate dehydrogenase complex, it also releases CO2 and produces NADH.

  5. Substrate-level Phosphorylation: Converts succinyl-CoA to succinate, producing GTP or ATP, catalyzed by succinyl-CoA synthetase.

  6. Oxidation: Succinate is oxidized to fumarate, generating FADH2, catalyzed by succinate dehydrogenase.

  7. Hydration: Converts fumarate to L-malate by adding water, catalyzed by fumarase.

  8. Final Oxidation: L-malate is oxidized back to oxaloacetate, producing another NADH, catalyzed by L-malate dehydrogenase, completing the cycle.

One Turn of the Citric Acid Cycle

  • Each cycle yields:

    • Three NADH

    • One FADH2

    • One GTP (or ATP)

    • Two CO2

  • Many reactions in the cycle are reversible, though some are thermodynamically irreversible.

Regulation of the Citric Acid Cycle

  • Regulated at irreversible steps, including:

    • Citrate synthase: Inhibited by ATP, NADH, and succinyl-CoA.

    • Isocitrate dehydrogenase: Inhibited by ATP and NADH; activated by ADP and NAD+.

    • α-ketoglutarate dehydrogenase: Inhibited by ATP, NADH, and succinyl-CoA; activated by ADP and NAD+.

  • Pyruvate dehydrogenase is also tightly regulated by ATP and NADH levels.

Citric Acid Cycle in Catabolism

  • The CAC receives inputs from protein, carbohydrate, and fatty acid catabolism, playing a vital role in the metabolic network.

B Vitamins and CAC

  • Essential B vitamins include:

    • B1 (Thiamine): Required for pyruvate to acetyl-CoA conversion.

    • B2 (Riboflavin): Precursor for FAD.

    • B3 (Niacin): Precursor for NAD+.

    • B5 (Pantothenic Acid): Component of CoA.

    • B6, B7, B9, B12 involved in various metabolic pathways.

Citric Acid Cycle in Anabolism

  • Provides precursors for biosynthesis; if intermediates are extracted, they must be replenished via anaplerotic reactions, like converting pyruvate to oxaloacetate.

Role of Pyruvate and Acetyl-CoA

  • In animals, acetyl-CoA is committed to the CAC; can’t revert to pyruvate.

  • Carbohydrates are the principal energy source, although carnivores can survive on protein and fats.

  • Plants can convert acetyl-CoA to other intermediates including pyruvate under specific conditions.

Link to Oxygen

  • The CAC is integral to aerobic metabolism, linking with oxidative phosphorylation and ETC to harness chemical energy to produce ATP.

  • NADH and FADH2 are crucial for transferring electrons to oxygen, facilitating energy production.