Tricarboxylic Acid Cycle Lecture Notes

Introduction

• Tricarboxylic Acid Cycle (TCA Cycle)
  • Also known as Krebs Cycle (named after Hans Krebs) and Citric Acid Cycle.
  • Discovered by Hans Krebs in 1937; Nobel Prize winner in 1953.
  • Citric acid identified by Oxtone in 1948.
  • Also called Metabolic Traffic Circle due to its central role in metabolism.

Significance

• Occurs in mitochondria.
• Final common oxidative pathway for carbohydrates, proteins, and fats into carbon dioxide.
• Produces reducing equivalents (NADH, FADH2) and ATP through substrate-level phosphorylation (GTP to ATP).
• Oxaloacetate acts as a catalyst, regenerating in the cycle.
• "Fat is burned on the wick of carbohydrates": Fat (Acetyl CoA) oxidation requires oxaloacetate from carbohydrates.
• Irreversible Reactions: Catalyzed by pyruvate dehydrogenase complex hinder the conversion of fat back to carbohydrates.
• Synthesis Roles
  • Non-essential amino acids
  • Heme and porphyrins
  • Purines and pyrimidines

Steps of TCA Cycle

• Eight steps in the mitochondrial matrix, catalyzed by eight enzymes.
  1. Acetyl CoA (2C) + Oxaloacetate (4C) → Citrate (6C) [Citrate Synthase]
  2. Citrate → Isocitrate (via cis-Aconitate) [Isomerization]
  3. Isocitrate → α-Ketoglutarate [Oxidative Decarboxylation]
  4. α-Ketoglutarate → Succinyl CoA [Oxidative Decarboxylation]
  5. Succinyl CoA → Succinate [Substrate-level Phosphorylation]
  6. Succinate → Fumarate [Dehydrogenation]
  7. Fumarate → Malate [Hydration]
  8. Malate → Oxaloacetate [Dehydrogenation]
• Energy Output per Acetyl CoA:
  • 3 NADH → 7.5 ATP
  • 1 FADH2 → 1.5 ATP
  • 1 GTP → 1 ATP
  • Total: 10 ATP per Acetyl CoA; 20 ATP per glucose molecule.

Inhibitors

• Mnemonic: FAMAKS
  • Aconitase inhibited by Fluoroacetate
  • α-Ketoglutarate Dehydrogenase inhibited by Arsenide
  • Succinate Dehydrogenase inhibited by Malonate

Regulation

• Dependent on substrate availability.
• Regulated by enzymes: Citrate Synthase, Isocitrate Dehydrogenase, α-Ketoglutarate Dehydrogenase.
• ATP inhibits pathway; ADP stimulates.

Amphibolic Role

• Catabolic: Oxidation of Acetyl CoA to CO2.
• Anabolic: Provides precursors for biosynthesis (e.g., amino acids, fatty acids).

Anaplerotic Reactions

• Replenish TCA cycle intermediates.
• Examples:
  • Pyruvate → Oxaloacetate [Pyruvate Carboxylase]
  • Glutamate → α-Ketoglutarate [Transamination/Deamination]
  • Propionyl CoA → Succinyl CoA (via Valine, Methionine, etc.)
  • Aspartate → Oxaloacetate [Transamination]

Summary

• TCA cycle is a vital metabolic pathway, central to energy production and biosynthesis.
• Includes regulation and inhibition mechanisms, as well as anabolic and catabolic roles.

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