Krebs Cycle Overview

Alternative Names

• Tricarboxylic Acid Cycle (TCA)
• Citric Acid Cycle
• Named after Hans Krebs

Preceding Steps

• Glycolysis: Converts glucose to pyruvate (2 pyruvates generated)
  • Products: 2 NADH, 2 ATP
• Transition Step: Conversion of pyruvate to Acetyl-CoA
  • Products: 2 NADH, 2 CO2 (decarboxylation)

Starting Molecules

• Acetyl-CoA: Formed from the transition step
• Oxaloacetate (OAA): 4-carbon molecule combined with Acetyl-CoA

Main Steps of the Krebs Cycle

1. Formation of Citrate

   • Enzyme: Citrate Synthase
   • Reaction: Acetyl-CoA + OAA → Citrate (6 carbons)
   • Regulation:
     • Inhibitors: ATP, NADH, Citrate, Succinyl-CoA
     • Stimulator: ADP

2. Conversion of Citrate to Isocitrate

   • Enzyme: Aconitase (reversible)
   • Function: Isomerization (shuffling of atoms)

3. Isocitrate to Alpha-Ketoglutarate

   • Enzyme: Isocitrate Dehydrogenase
   • Reaction: Isocitrate (6C) → Alpha-Ketoglutarate (5C) + CO2 (decarboxylation)
   • Products: NADH generated
   • Regulation:
     • Inhibitors: ATP
     • Stimulators: ADP, Calcium

4. Alpha-Ketoglutarate to Succinyl-CoA

   • Enzyme: Alpha-Ketoglutarate Dehydrogenase
   • Reaction: Alpha-Ketoglutarate (5C) → Succinyl-CoA (4C) + CO2 (decarboxylation)
   • Products: NADH generated
   • Regulation:
     • Inhibitors: Succinyl-CoA, NADH
     • Stimulator: Calcium

5. Succinyl-CoA to Succinate

   • Enzyme: Succinyl-CoA Synthetase
   • Reaction: Succinyl-CoA → Succinate + CoA + GTP
   • Products: ATP generated by substrate-level phosphorylation

6. Succinate to Fumarate

   • Enzyme: Succinate Dehydrogenase (part of the electron transport chain)
   • Reaction: Succinate → Fumarate + FADH2
   • Importance: Mutations can lead to pheochromocytoma (tumor in adrenal medulla)

7. Fumarate to Malate

   • Enzyme: Fumarase
   • Reaction: Fumarate + H2O → Malate (reversible)

8. Malate to Oxaloacetate

   • Enzyme: Malate Dehydrogenase
   • Reaction: Malate → OAA + NADH (reversible)

Summary of Outputs

• From 2 Acetyl-CoA (2 turns of the cycle):
  • 4 CO2 generated
  • 6 NADH generated
  • 2 FADH2 generated
  • 2 ATP generated (substrate-level phosphorylation)

Key Regulatory Points

• ATP, NADH, and succinyl-CoA act as inhibitors at different steps.
• ADP and calcium act as stimulators to promote the cycle when energy is low.
• Importance of maintaining balance in the cycle for metabolic control.

Clinical Relevance

• Mutations in key enzymes can lead to cancer (e.g., gliomas from alpha-ketoglutarate dehydrogenase mutation).

Conclusion

• The Krebs cycle is crucial for cellular respiration, generating ATP and reducing equivalents (NADH, FADH2) for the electron transport chain.