Krebs Cycle Overview Lecture Notes

Introduction

• The Krebs cycle, also known as the Tricarboxylic Acid (TCA) cycle or Citric Acid Cycle.
• Discovered by Hans Krebs.
• Preceded by glycolysis which converts glucose to two pyruvates, generating 2 NADH and 2 ATP.
• In presence of oxygen, pyruvate enters mitochondria and is converted to Acetyl-CoA.

Formation of Acetyl-CoA

• Transition step:
  • Coenzyme A added to pyruvate.
  • Generates 2 NADH and 2 CO2 via pyruvate dehydrogenase complex (E1, E2, E3).

Krebs Cycle Steps

1. Acetyl-CoA + Oxaloacetate → Citrate

   • Catalyzed by Citrate Synthase.
   • Irreversible step.
   • Regulation:
     • Inhibited by ATP, NADH, and excess citrate.
     • Stimulated by ADP.

2. Citrate → Isocitrate

   • Catalyzed by Aconitase.
   • Reversible step.
   • Sensitive to fluoroacetate (rat poison).

3. Isocitrate → α-Ketoglutarate

   • Catalyzed by Isocitrate Dehydrogenase.
   • Produces CO2 and NADH.
   • Regulated by:
     • Inhibited by ATP.
     • Stimulated by ADP and Calcium.

4. α-Ketoglutarate → Succinyl-CoA

   • Catalyzed by α-Ketoglutarate Dehydrogenase.
   • Produces CO2 and NADH.
   • Regulated by:
     • Inhibited by Succinyl-CoA and NADH.
     • Stimulated by Calcium.

5. Succinyl-CoA → Succinate

   • Catalyzed by Succinyl-CoA Synthetase.
   • Generates GTP which is converted to ATP.
   • Example of substrate-level phosphorylation.

6. Succinate → Fumarate

   • Catalyzed by Succinate Dehydrogenase.
   • Produces FADH2.
   • Part of the electron transport chain (Complex II).

7. Fumarate → Malate

   • Catalyzed by Fumarase.
   • Involves addition of water.

8. Malate → Oxaloacetate

   • Catalyzed by Malate Dehydrogenase.
   • Produces NADH.

Additional Notes

• Mnemonic: "Citrate Is Krebs Starting Substrate For Making Oxaloacetate" helps in memorizing the cycle.
• Enzymes are subject to allosteric regulation based on energy levels (ATP/ADP ratio) and presence of cycle intermediates.
• Potential Inhibitors:
  • Rat poison (fluoroacetate) affecting Aconitase.
  • Mutations in enzymes can lead to diseases, e.g., mutations in alpha-ketoglutarate dehydrogenase can lead to tumor formation.

Products of Krebs Cycle

• 2 turns of the cycle per glucose molecule:
  • 4 CO2
  • 6 NADH
  • 2 FADH2
  • 2 ATP
• These products enter the electron transport chain to produce ATP through oxidative phosphorylation.

Conclusion

• The Krebs cycle is a central metabolic pathway that produces energy carriers used for ATP synthesis.
• Regulatory steps ensure energy production is balanced with cellular needs.