Lecture Notes: PDH and TCA Cycle

Introduction

• Understanding the importance of metabolic pathways in cellular processes.
• Focus on Pyruvate Dehydrogenase (PDH) complex and the Tricarboxylic Acid (TCA) Cycle.

Pyruvate Dehydrogenase (PDH) Complex

• Function: Converts pyruvate into acetyl-CoA, a critical step linking glycolysis to the TCA cycle.
• Location: Mitochondrial matrix.
• Components: Multi-enzyme complex including E1, E2, and E3 enzymes.
  • E1 (Pyruvate decarboxylase): Decarboxylation of pyruvate.
  • E2 (Dihydrolipoamide transacetylase): Transfers the acetyl group.
  • E3 (Dihydrolipoamide dehydrogenase): Regeneration of lipoamide.
• Regulation:
  • Allosteric inhibition by ATP, acetyl-CoA, and NADH.
  • Activation by ADP and pyruvate.
  • Covalent modification via phosphorylation (inactive) and dephosphorylation (active).

Tricarboxylic Acid (TCA) Cycle

• Also known as: Citric Acid Cycle or Krebs Cycle.
• Purpose: Completes the oxidation of glucose by breaking down acetyl-CoA into CO2 and capturing high-energy electrons in NADH and FADH2.

Key Steps

1. Citrate Formation: Acetyl-CoA combines with oxaloacetate to form citrate.
2. Isomerization: Citrate is converted to isocitrate.
3. First Oxidation: Isocitrate is oxidized to α-ketoglutarate, releasing CO2 and reducing NAD+ to NADH.
4. Second Oxidation: α-ketoglutarate is oxidized to succinyl-CoA, releasing another CO2 and producing NADH.
5. Substrate-level Phosphorylation: Succinyl-CoA converted to succinate, producing GTP (or ATP).
6. Third Oxidation: Succinate is oxidized to fumarate, reducing FAD to FADH2.
7. Hydration: Fumarate is hydrated to malate.
8. Fourth Oxidation: Malate is oxidized to oxaloacetate, yielding NADH.

Regulation

• Allosteric Regulation:
  • Inhibition by high levels of ATP, NADH.
  • Activation by ADP and NAD+.
• Key Enzymes Regulated: Isocitrate dehydrogenase, α-ketoglutarate dehydrogenase.

Importance of PDH and TCA Cycle

• Central roles in energy production.
• Provide precursors for biosynthetic pathways.
• Integration point for various metabolic pathways.

Clinical Relevance

• Disorders such as PDH deficiency affect energy metabolism.
• Potential targets for treating metabolic diseases and cancer.

Summary

• The PDH complex serves as a bridge between glycolysis and the TCA cycle.
• The TCA cycle is crucial for complete glucose oxidation and energy production.
• Both are tightly regulated to meet cellular energy demands.