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Key Concepts of the Citric Acid Cycle

Introduction to the Citric Acid Cycle

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

  • Central pathway for energy recovery from carbohydrates, fats, and proteins.

  • Plays a dual role in catabolism (energy production) and anabolism (biosynthesis).

Overview of Catabolic Processes

  • Stage 1: Glycolysis generates pyruvate from glucose.

  • Stage 2: Produces Acetyl-CoA from pyruvate via the Pyruvate Dehydrogenase complex, releasing CO₂ and generating NADH.

  • Stage 3: Acetyl-CoA enters the TCA cycle, leading to further CO₂ release and generating NADH, FADH₂, and ATP.

Amphibolic Nature of the Citric Acid Cycle

  • The cycle is called amphibolic because it serves both as a catabolic pathway (energy production) and an anabolic pathway (building blocks for biomolecules).

  • Intermediates from the cycle can also act as precursors for various biosynthetic pathways (e.g., amino acids, fatty acids).

Key Intermediates and Anaplerotic Reactions

  • Intermediates such as Citrate, Oxaloacetate, and Succinyl-CoA serve as building blocks for:

    • Gluconeogenesis (Malate to Glucose)

    • Lipid Biosynthesis (Citrate to Acetyl-CoA to Lipids)

    • Amino Acid Biosynthesis (e.g., OAA forms aspartate)

    • Porphyrin Biosynthesis (Succinyl-CoA)

The Mitochondrial Environment

  • Outer Membrane: Permeable to small molecules (≤ 5 kD).

  • Inner Membrane: Selective permeability; requires transport proteins for larger molecules.

  • Location of the TCA Cycle: Entirely within the mitochondria.

Steps of the Citric Acid Cycle

  1. Formation of Citrate: Acetyl-CoA combines with Oxaloacetate to form Citrate, while CoA is released.

  2. Isomerization to Isocitrate: A two-step process involving dehydration and rehydration.

  3. Oxidative Decarboxylation of Isocitrate: Produces $CO₂$ and $NADH$, yielding a-ketoglutarate.

  4. Oxidation of a-Ketoglutarate: Similar to Pyruvate Dehydrogenase, producing Succinyl-CoA, another $NADH$, and $CO₂$.

  5. Conversion of Succinyl-CoA to Succinate: Generates GTP/ATP from the high-energy thioester bond.

  6. Oxidation of Succinate: Electrons flow from FAD to the electron transport chain; this produces FADH₂.

  7. Hydration of Fumarate: Water is added to fumarate to form malate.

  8. Final Oxidation of Malate: Hydride transferred to $NAD^+$ to produce the last $NADH$ and regenerate Oxaloacetate.

Energy Yield from TCA Cycle

  • Each cycle results in:

    • 3 $NADH$

    • 1 $FADH₂$

    • 1 GTP (or ATP)

    • 2 $CO₂$

Regulation of the Citric Acid Cycle

  • Key regulatory points at the three exergonic (energy-releasing) steps:

    1. Pyruvate Dehydrogenase Complex: Regulated by ATP, Acetyl-CoA, and NADH (inhibitory) as well as AMP and Ca²⁺ (stimulatory).

    2. Citrate Synthase: Inhibited by NADH, Succinyl-CoA, and Citrate; activated by ADP.

    3. Isocitrate Dehydrogenase: Activated by Ca²⁺ and ADP, inhibited by NADH.

    4. a-Ketoglutarate Dehydrogenase Complex: Similar regulation as PDH, also affected by Ca²⁺.

    5. Succinate Dehydrogenase: Regulated by Succinyl-CoA and GTP/ATP.

Summary of Key Products

  • The citric acid cycle produces:

    • Energy carriers: $NADH$, $FADH₂$, GTP/ATP

    • By-products: $CO₂$, $H₂O$

  • Central to both energy production and biosynthesis, making it a vital metabolic pathway.