chapter19

Overview of the Citric Acid Cycle

  • Authors: Mary K. Campbell, Shawn O. Farrell

  • Source: Cengage

  • Chapter Overview: Introduction to the Citric Acid Cycle, also known as the Krebs Cycle.

The Central Role of the Citric Acid Cycle

  • Key Processes in Aerobic Metabolism:

    • Citric Acid Cycle (CAC)

    • Electron Transport Chain

    • Oxidative Phosphorylation

  • Definitions of Metabolism:

    • Catabolism: Breakdown of nutrients for energy.

    • Anabolism: Synthesis of biomolecules.

  • Functionality of the CAC:

    • Amphibolic in nature; contributes to both catabolism and anabolism.

    • Central metabolic pathway

Central Relationship to Catabolism

  • Stages of Catabolism:

    1. Production of Acetyl-CoA:

      • Derived from amino acids, fatty acids, and glucose.

    2. CAC Entry: Acetyl-CoA enters the citric acid cycle.

    3. Electron Transport: Generates ATP using electrons.

Cellular Respiration and the CAC

  • Cellular Respiration: The CAC is the initial stage where high-energy electrons are removed from carbon fuels, subsequently reducing O2 and generating ATP through oxidative phosphorylation.

Location of the Citric Acid Cycle

  • Eukaryotes: Takes place in the mitochondrial matrix.

Pathway from Glucose to Acetyl-CoA

  • Enzymatic Conversion:

    • Pyruvate from glycolysis is transformed into acetyl-CoA through the Pyruvate Dehydrogenase Complex (PDH).

  • Significance: This process is irreversible and crucial in glucose metabolism.

Structure and Function of Pyruvate Dehydrogenase Complex

  • Components: Five enzymes involved:

    • Pyruvate Dehydrogenase

    • Dihydrolipoyl Transacetylase

    • Dihydrolipoyl Dehydrogenase

    • Pyruvate Dehydrogenase Kinase

    • Pyruvate Dehydrogenase Phosphatase

  • Process: Pyruvate loses CO2 and forms Acetyl-CoA through a series of steps involving the above enzymes, leading to acetyl transfer to CoA.

Mechanism of Pyruvate Dehydrogenase Complex

  1. Decarboxylation of Pyruvate: Produces hydroxyethyl-TPP (HETPP).

  2. Transfer to Lipoic Acid: Hydroxyethyl group is oxidized and transferred.

  3. Transfer to CoA: Acetyl group is transferred to CoA.

  4. Reoxidation of Dihydrolipoamide: Recycles the cofactor.

The Citric Acid Cycle Reactions

  • Overall Reactions: Summary of the 8 enzymatic reactions that illustrate the cyclical nature of substrate transformations within the CAC.

  • Energy Yielding Reactions: Identifies key steps that yield NADH, FADH2, and GTP/ATP throughout the cycle.

Energetics of the Citric Acid Cycle

  • Free Energy Changes: Notable energy transformations accompany each step within the cycle.

  • Stoichiometric Relationships: Information on overall ATP yield per glucose molecule via cyclical processes in aerobic glycolysis and subsequent metabolism via the CAC.

Regulation of the Citric Acid Cycle

  • Key Points of Control:

    • Citrate Synthase: Inhibited by ATP and NADH.

    • Isocitrate Dehydrogenase: Activated by ADP; inhibited by ATP and NADH.

    • α-Ketoglutarate Dehydrogenase: Inhibited by ATP; activated by ADP and NAD+.

  • External Control Point: The pyruvate dehydrogenase complex is also regulated similarly.

Glyoxylate Cycle

  • Alternative Pathway: Modifications in plants and certain bacteria to produce glucose using dicarboxylic acids, allowing energy generation from the oxidation of fatty acids during germination.

Anabolic Roles of the Citric Acid Cycle

  • Biosynthesis Source: Components serve as precursors in the synthesis of amino acids, fatty acids, and glucose.

  • Anaplerotic Reactions: Mechanisms that replenish cycle intermediates and the cycling pathways involved.

Summary of Key Points

  • The citric acid cycle is integral to both anabolic and catabolic pathways. Nutrients break down into component parts that feed into the cycle, while intermediates can be diverted to synthesize vital biomolecules. Its connectivity to oxidative phosphorylation ties it crucially to aerobic respiration and energy production.


Detailed Overview of the 8 Enzymatic Reactions of the Citric Acid Cycle

  1. Citrate Synthase

    • Reaction: Acetyl-CoA + Oxaloacetate → Citrate

    • Details: The enzyme combines Acetyl-CoA and oxaloacetate to form citrate. This is a condensation reaction involving the release of CoA and utilizes a high-energy thioester bond in Acetyl-CoA.

  2. Aconitase

    • Reaction: Citrate ↔ Cis-Aconitate ↔ Isocitrate

    • Details: Aconitase catalyzes the isomerization of citrate to isocitrate via cis-aconitate. The process involves the removal and re-addition of water (dehydration followed by hydration).

  3. Isocitrate Dehydrogenase

    • Reaction: Isocitrate + NAD^+ → α-Ketoglutarate + CO2 + NADH

    • Details: This reaction is oxidative decarboxylation. Isocitrate is oxidized, reducing NAD^+ to NADH and simultaneously releasing CO2.

  4. α-Ketoglutarate Dehydrogenase

    • Reaction: α-Ketoglutarate + NAD^+ + CoA → Succinyl-CoA + CO2 + NADH

    • Details: Another oxidative decarboxylation, in which α-ketoglutarate undergoes a reaction similar to pyruvate dehydrogenation, producing succinyl-CoA and releasing CO2.

  5. Succinyl-CoA Synthetase

    • Reaction: Succinyl-CoA + GDP (or ADP) + Pi → Succinate + CoA + GTP (or ATP)

    • Details: This enzyme catalyzes the substrate-level phosphorylation of GDP to GTP (or ADP to ATP), accompanied by the release of CoA from succinyl-CoA.

  6. Succinate Dehydrogenase

    • Reaction: Succinate + FAD → Fumarate + FADH2

    • Details: Succinate is oxidized to fumarate, reducing FAD to FADH2 in the process. This enzyme is unique as it is embedded in the inner mitochondrial membrane.

  7. Fumarase (Fumarate Hydratase)

    • Reaction: Fumarate + H2O → Malate

    • Details: This enzyme catalyzes the reversible hydration of fumarate to malate, involving the addition of a water molecule.

  8. Malate Dehydrogenase

    • Reaction: Malate + NAD^+ → Oxaloacetate + NADH

    • Details: The final reaction in the cycle converts malate back to oxaloacetate, generating NADH and completing the cycle. This step is also reversible and contributes to the cycle's energy balance.