Krebs Cycle (Citric Acid Cycle/Tricarboxylic Acid Cycle)

Overview

• Discovered by Hans Krebs.
• Alternative names: Citric Acid Cycle, Tricarboxylic Acid Cycle.
• Follows glycolysis, which converts glucose into two pyruvates.
• With oxygen, pyruvates enter mitochondria, transitioning to the Krebs cycle after pyruvate dehydrogenase complex (producing 2 NADH, 2 CO2).
• Acetyl CoA is formed and enters the Krebs cycle.

Steps of the Krebs Cycle

1. Formation of Citrate

   • Acetyl CoA (2-carbon) combines with oxaloacetate (4-carbon) to form citrate (6-carbon).
   • Enzyme: Citrate Synthase.
   • Not reversible and highly regulated.

2. Conversion of Citrate to Isocitrate

   • Enzyme: Aconitase.
   • Isomerization reaction (reversible).
   • Inhibited by fluoroacetate from rat poison.

3. Isocitrate to Alpha-Ketoglutarate

   • Enzyme: Isocitrate Dehydrogenase.
   • Produces NADH and CO2 (decarboxylation).
   • Regulated by ATP (inhibits), ADP (stimulates), and Calcium (stimulates).

4. Alpha-Ketoglutarate to Succinyl CoA

   • Enzyme: Alpha-Ketoglutarate Dehydrogenase.
   • Produces NADH and CO2 (decarboxylation).
   • Regulation by NADH (inhibits) and Calcium (stimulates).

5. Succinyl CoA to Succinate

   • Enzyme: Succinyl CoA Synthase.
   • Produces GTP through substrate-level phosphorylation, converted to ATP.

6. Succinate to Fumarate

   • Enzyme: Succinate Dehydrogenase (part of Electron Transport Chain, Complex II).
   • Produces FADH2.
   • Mutations can cause pheochromocytoma.

7. Fumarate to Malate

   • Enzyme: Fumarase.
   • Addition of water.
   • Deficiency can lead to leiomyomas.

8. Malate to Oxaloacetate

   • Enzyme: Malate Dehydrogenase.
   • Produces NADH.

Regulatory Aspects

• Citrate Synthase Regulation: Inhibited by ATP, NADH, succinyl CoA; stimulated by ADP.
• Isocitrate Dehydrogenase Regulation: Inhibited by ATP; stimulated by ADP and Calcium.
• Alpha-Ketoglutarate Dehydrogenase Regulation: Inhibited by NADH and succinyl CoA; stimulated by Calcium.

Key Mnemonic

• "Citrate Is Krebs Starting Substrate For Making Oxaloacetate":
  • Citrate
  • Isocitrate
  • Alpha-Ketoglutarate
  • Succinyl CoA
  • Succinate
  • Fumarate
  • Malate
  • Oxaloacetate

Products of the Krebs Cycle for 2 Acetyl CoA

• 4 CO2
• 6 NADH
• 2 FADH2
• 2 ATP via substrate-level phosphorylation

Additional Notes

• Alpha-Ketoglutarate is crucial for histone demethylase, involved in gene expression.
• Two hydroxyglutarate, a mutation byproduct, can inhibit gene expression, leading to tumor formation (gliomas).

Conclusion

• The Krebs cycle is essential in cellular respiration, converting biochemical energy from nutrients into ATP, with regulatory mechanisms ensuring energy production matches cellular needs.