Krebs Cycle Lecture Notes

Overview

• Also known as:
  • Tricarboxylic acid cycle
  • Citric acid cycle
• Discovered by Hans Krebs
• Detailed discussion on glycolysis and the transition to the Krebs cycle

Glycolysis Recap

• Glucose conversion into 2 pyruvates
• Produced:
  • 2 NADH
  • 2 net ATP
• Pyruvate enters mitochondria with oxygen, changes to Acetyl-CoA
  • Generates 2 NADH and 2 CO2
• Transition step involves Pyruvate Dehydrogenase Complex (E1, E2, E3)

Transition to Krebs Cycle

• Acetyl-CoA (from transition) joins with Oxaloacetate (OAA) to form Citrate
  • OAA: 4-carbon structure
  • Acetyl-CoA: 2-carbon structure
• Forms a 6-carbon structure (Citrate)

Mnemonic for Intermediates

• "Citrate is Krebs Starting Substrate For Making Oxaloacetate"
  • C: Citrate
  • I: Isocitrate
  • K: Alpha-ketoglutarate
  • S: Succinyl-CoA
  • S: Succinate
  • F: Fumarate
  • M: Malate
  • O: Oxaloacetate

Enzymatic Reactions

1. Citrate Synthase

   • Combines Acetyl-CoA and OAA to form Citrate
   • Regulated by:
     • Inhibition: High ATP, NADH, Citrate, Succinyl-CoA
     • Stimulation: ADP

2. Aconitase

   • Converts Citrate to Isocitrate (isomerization)
   • Reversible reaction
   • Inhibited by Fluoroacetate (rat poison)

3. Isocitrate Dehydrogenase

   • Converts Isocitrate to Alpha-ketoglutarate
   • Produces CO2 and NADH
   • Regulated by:
     • Inhibition: ATP
     • Stimulation: ADP, Calcium

4. Alpha-ketoglutarate Dehydrogenase

   • Converts Alpha-ketoglutarate to Succinyl-CoA
   • Produces CO2 and NADH
   • Regulated by:
     • Inhibition: Succinyl-CoA, NADH
     • Stimulation: Calcium

5. Succinyl-CoA Synthetase

   • Converts Succinyl-CoA to Succinate
   • Generates GTP (turned into ATP)
   • Substrate-level phosphorylation

6. Succinate Dehydrogenase

   • Converts Succinate to Fumarate
   • Produces FADH2
   • Part of the electron transport chain (Complex II)

7. Fumarase

   • Converts Fumarate to Malate
   • Adds water molecule

8. Malate Dehydrogenase

   • Converts Malate to Oxaloacetate
   • Produces NADH

Total Yield from Krebs Cycle (per 2 turns)

• 4 CO2
• 6 NADH
• 2 FADH2
• 2 ATP (substrate phosphorylation)

Importance and Regulation

• Allosteric regulation based on energy supply (ATP, NADH, ADP)
• Mutations in enzymes can lead to metabolic and health issues (e.g., tumors, pheochromocytoma)

Conclusion

• The Krebs cycle is integral for energy production, feeding into the electron transport chain for ATP synthesis.
• Enzymes in the pathway are tightly regulated to maintain balance in cellular metabolism.