The Krebs Cycle (Citric Acid Cycle)

Overview

• Also known as the Tricarboxylic Acid Cycle or Citric Acid Cycle.
• Discovered by Hans Krebs.
• Fire detail understanding of previous cellular respiration steps like Glycolysis and Pyruvate conversion are assumed.

Key Points

Pre-Krebs Cycle

• Glycolysis Recap: Glucose (6C) → 2 Pyruvate (3C each) → 2 NADH + 2 ATP (net)
• Pyruvate to Acetyl-CoA: Pyruvate enters mitochondria, forming 2 Acetyl-CoA, 2 NADH, and 2 CO2 (via Pyruvate Dehydrogenase Complex)

The Krebs Cycle Steps

1. **Formation of Citrate: (6C)

   • Reactants: Acetyl-CoA (2C) + Oxaloacetate (4C).
   • Enzyme: Citrate Synthase.
   • Mnemonic: Citrate Is Krebs Starting Substrate For Making Oxaloacetate.

2. **Isomerization to Isocitrate (6C)

   • Enzyme: Aconitase.
   • Converts citrate to isocitrate by shifting H and OH positions.

3. **Isocitrate to α-Ketoglutarate (5C)

   • Enzyme: Isocitrate Dehydrogenase.
   • Process: Decarboxylation (loss of CO2) & Reduction (NAD+ to NADH).
   • Regulation: Inhibited by ATP, NADH; Stimulated by ADP, Ca2+.

4. **α-Ketoglutarate to Succinyl-CoA (4C)

   • Enzyme: α-Ketoglutarate Dehydrogenase.
   • Process: Decarboxylation (loss of CO2) & Reduction (NAD+ to NADH).
   • Regulation: Inhibited by Succinyl-CoA, NADH; Stimulated by Ca2+.

5. **Succinyl-CoA to Succinate (4C)

   • Enzyme: Succinyl-CoA Synthetase.
   • Process: Formation of GTP (later converted to ATP via substrate-level phosphorylation).

6. **Succinate to Fumarate (4C)

   • Enzyme: Succinate Dehydrogenase.
   • Process: FAD to FADH2.

7. **Fumarate to Malate (4C)

   • Enzyme: Fumarase.
   • Process: Hydration (addition of H2O).

8. **Malate to Oxaloacetate (4C)

   • Enzyme: Malate Dehydrogenase.
   • Process: Reduction (NAD+ to NADH).

Products per Acetyl-CoA (Turn of Cycle)

• Total Generated: 2 cycles for glucose (due to 2 Acetyl-CoAs from 1 Glucose).
• NADH: 3 per cycle (6 per glucose).
• FADH2: 1 per cycle (2 per glucose).
• GTP/ATP: 1 per cycle (2 per glucose).
• CO2: 2 per cycle (4 per glucose).

Regulation Highlights

• Inhibition: High levels of ATP, NADH, Succinyl-CoA, and Citrate.
• Stimulation: High levels of ADP, AMP, Ca2+.

Additional Notes

• Role in Metabolism: Key for energy production, and provides intermediates for biosynthesis pathways.
• Clinical Significance: Mutations/deficiencies can lead to disorders like tumors (gliomas), and diseases like Pheochromocytoma.

Mnemonics

• Citrate is Krebs Starting Substrate For Making Oxaloacetate.
• Can be used to recall intermediates: Citrate → Isocitrate → α-Ketoglutarate → Succinyl-CoA → Succinate → Fumarate → Malate → Oxaloacetate.