Krebs Cycle Lecture Notes

Overview

• Krebs Cycle is also known as the Citric Acid Cycle or Tricarboxylic Acid Cycle.
• Developed by Hans Krebs.
• Key step after glycolysis when oxygen is present.

Glycolysis Review

• Converts glucose into 2 pyruvate molecules.
• Produces 2 NADH and 2 net ATP.
• Pyruvate enters mitochondria if oxygen is present, preparing for Krebs cycle through:
  • Addition of Coenzyme A
  • Production of 2 NADH and 2 CO2 via decarboxylation

Krebs Cycle Steps

1. Formation of Citrate
   • Substrates: Acetyl CoA (2-carbon) + Oxaloacetate (OAA, 4-carbon)
   • Enzyme: Citrate synthase
   • Product: Citrate (6-carbon)
   • Mnemonic: Citrate is Krebs starting substrate for making Oxaloacetate
2. Isomerization of Citrate to Isocitrate
   • Enzyme: Aconitase
3. Formation of α-ketoglutarate
   • Substrate: Isocitrate (6-carbon)
   • Enzyme: Isocitrate dehydrogenase
   • Process: Decarboxylation & dehydrogenation
   • Products: α-ketoglutarate (5-carbon), CO2, NADH
   • Regulation: Inhibited by ATP & NADH, stimulated by ADP & calcium
4. Formation of Succinyl CoA
   • Substrate: α-ketoglutarate (5-carbon)
   • Enzyme: α-ketoglutarate dehydrogenase
   • Process: Decarboxylation & dehydrogenation
   • Products: Succinyl CoA (4-carbon), CO2, NADH
   • Regulation: Inhibited by succinyl CoA & NADH, stimulated by calcium
5. Formation of Succinate
   • Enzyme: Succinyl CoA synthetase
   • Process: Substrate-level phosphorylation
   • Products: Succinate (4-carbon), ATP (or GTP)
6. Formation of Fumarate
   • Enzyme: Succinate dehydrogenase (Complex II of ETC)
   • Process: Dehydrogenation
   • Products: Fumarate, FADH2
   • Reversible: Part of ETC
7. Formation of Malate
   • Enzyme: Fumarase
   • Process: Hydration
   • Products: Malate
   • Reversible
8. Regeneration of Oxaloacetate
   • Enzyme: Malate dehydrogenase
   • Process: Dehydrogenation
   • Products: Oxaloacetate, NADH
   • Reversible

Products for Each Turn

• ATP/GTP: 1
• NADH: 3
• FADH2: 1
• CO2: 2
• Total (Two Turns):
  • NADH: 6
  • FADH2: 2
  • ATP/GTP: 2
  • CO2: 4

Regulation

• Key enzymes regulated by availability of substrates & feedback inhibition.
• Inhibitors: ATP, NADH, Citrate, Succinyl CoA
• Stimulators: ADP, Calcium

Important Concepts

• Allosteric Regulation: Enzymes can be inhibited or stimulated based on cellular energy levels.
• Substrate-Level Phosphorylation: Direct formation of ATP from intermediates.
• Oxidative Phosphorylation: Major ATP production using electrons from NADH & FADH2.
• Clinical Relevance: Mutations in the cycle enzymes can lead to metabolic diseases and cancer (e.g., mutations causing 2-hydroxyglutarate formation leading to cancer).