Pyruvate dehydrogenase complex

  • Mitochondrial enzyme complex linking glycolysis and TCA cycle. Differentially regulated in fed/fasting states (active in fed state).
  • Reaction: pyruvate + NAD+ + CoA → acetyl-CoA + CO2 + NADH.
  • The complex contains 3 enzymes that require 5 cofactors:
    1. Thiamine pyrophosphate (B1)
    2. Lipoic acid
    3. CoA (B5, pantothenic acid)
    4. FAD (B2, riboflavin)
    5. NAD+ (B3, niacin)
  • Activated by:
    • ↑ NAD+/NADH ratio
    • ↑ ADP
    • ↑ Ca2+
  • The complex is similar to the α-ketoglutarate dehydrogenase complex (same cofactors, similar substrate and action), which converts α-ketoglutarate → succinyl-CoA (TCA cycle).
  • The Lovely Co-enzymes For Nerds.
  • Arsenic inhibits lipoic acid. Binds to sulfhydryl groups, impairing cellular respiration via pyruvate dehydrogenase inhibition, disruption of gluconeogenesis & glutathione metabolism. Arsenic poisoning clinical findings: imagine a vampire (pigmentary skin changes, skin cancer), vomiting and having diarrhea, running away from a cutie (QT prolongation) with garlic breath. Treat with dimercaprol (sulfhydryl group chelation), but has narrow therapeutic index (SE: nephrotoxicity, hypertension, fever); or DMSA (meso-2,3-dimercaptosuccinic acid, succimer)

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