Pyruvate Dehydrogenase and Acetyl CoA Formation

One-way Traffic of Metabolism

  • One-way traffic facilitates metabolic pathways and directs metabolites to specific locations.
  • Pyruvate Dehydrogenase (PDH): The enzyme complex that links glycolysis to cellular respiration, facilitating the conversion of pyruvate into acetyl CoA.

Pyruvate Conversion Pathways

  • Anaerobic Conditions: Pyruvate can be converted to lactic acid or ethanol, depending on the organism.
  • Aerobic Conditions: Pyruvate is transformed into Acetyl CoA, which enters the citric acid cycle (CAC). The choice between these pathways depends on cellular energy demand and oxygen availability.
    • Example:
    • Resting Human Muscle: Mostly aerobic metabolism.
    • Active Muscle (e.g. sprinter's thigh): Pyruvate is converted to lactate due to insufficient oxygen.

Acetyl Coenzyme A and the Citric Acid Cycle

  • Acetyl CoA serves as the principal fuel for the citric acid cycle.
  • Key Functions:
    • Accepts two-carbon acetyl units through formation via linkage with a four-carbon molecule.
    • The oxidization of these units generates high-transfer-potential electrons as well as ATP.
  • PDH activity is crucial to initiate acetyl CoA production from pyruvate and subsequently to feed into the CAC.

Mechanism of Pyruvate Dehydrogenase Complex (PDC)

  • Location: Glycolysis occurs in the cytoplasm while the citric acid cycle occurs in the mitochondria.
  • Pyruvate is oxidatively decarboxylated in the mitochondrial matrix to form acetyl CoA, making it a key junction in metabolism.
  • The irreversible conversion of pyruvate to acetyl CoA decides its fate toward oxidation or fatty acid synthesis.

Composition of PDC

  • The PDC consists of three enzymes:
    1. Pyruvate Dehydrogenase (PDH)
    2. Dihydrolipoyl Transacetylase
    3. Dihydrolipoyl Dehydrogenase
  • These enzymes are integrated into a single large complex.
  • Each enzyme facilitates specific reactions in the conversion pathway:
    • Decarboxylation: Catalyzed by PDH forming hydroxyethyl-TPP.
    • Oxidation: Transfer to lipoamide forming acetyl-lipoamide.
    • Formation of Acetyl CoA: Transfer to CoA catalyzed by Dihydrolipoyl Transacetylase.

Requirements for Acetyl CoA Production

  • Cofactors Needed:
    • Thiamine Pyrophosphate (TPP): Catalytic coenzyme for PDH.
    • Lipoic Acid: Participates in oxidation-reduction.
    • Flavin Adenine Dinucleotide (FAD): Acts as a cofactor for regeneration of lipoamide.
    • Coenzyme A (CoA) and Nicotinamide Adenine Dinucleotide (NAD).
  • Mechanistic Overview:
    • Decarboxylation, oxidation, acetyl group transfer occurs in a tightly coupled manner to conserve energy.

Regulation of Pyruvate Dehydrogenase Complex

  • Regulatory Mechanisms:
    • Allosteric interactions and covalent modifications (especially phosphorylation) play a role.
    • Inhibitors: Acetyl CoA and NADH signal sufficient energy in the cell, inhibiting PDH activity to prevent excess substrates.
    • Activation: Low energy conditions (high levels of ADP and pyruvate) stimulate enzyme activity by inhibiting the kinase that phosphorylates PDH.

Phosphorylation and Deactivation

  • Pyruvate Dehydrogenase Kinase: Phosphorylates and inactivates PDH.
  • Pyruvate Dehydrogenase Phosphatase: Activates PDH by dephosphorylation.
  • High ATP concentrations activate kinase leading to PDH inactivation, especially when muscle energy demands are minimal.

Clinical Insights

  • Lactic Acidosis: Caused by PDH dysfunction leading to pyruvate being converted to lactate instead of acetyl CoA under low oxygen conditions.
  • Beriberi: A condition related to thiamine deficiency impacting PDH activity, leading to neurological disorders due to impaired energy metabolism in nerves.
  • Cancer Metabolism: Enhanced activity of Pyruvate Dehydrogenase Kinase may facilitate the cancer characteristic of aerobic glycolysis (Warburg effect).
  • Mercury and Arsenite Toxicity: Both inhibit PDH activity causing systemic dysfunction, especially in the nervous system.