8 (R)

Acetyl-CoA

Central metabolic intermediate linking glycolysis, fatty acid breakdown, amino acid metabolism to citric acid cycle, and carbohydrate metabolism to lipid synthesis.

Pyruvate → Acetyl-CoA

Catalyzed by Pyruvate Dehydrogenase (PDH) Complex; irreversible, highly regulated, commits carbon to oxidation; net reaction: Pyruvate + CoA + NAD⁺ → Acetyl-CoA + CO₂ + NADH.

PDH Cofactors

TPP (B1), Lipoate, CoA (B5), FAD (B2), NAD⁺ (B3); essential for PDH activity; deficiency impairs acetyl-CoA production.

High-Yield PDH Concepts

Reaction irreversible; produces CO₂ and NADH; 3 enzymes: E1 decarboxylation, E2 acetyl transfer, E3 electron transfer; substrate channeling via lipoyl swinging arm.

Committed step of PDH

Once pyruvate is converted to acetyl-CoA, carbon cannot return to glucose; explains why fatty acids cannot produce glucose.

Citrate Synthase

Condenses acetyl-CoA + oxaloacetate → citrate; key regulatory step of TCA; inhibited by ATP, NADH, citrate, succinyl-CoA; activated by ADP.

Isocitrate Dehydrogenase

Converts isocitrate → α-ketoglutarate + NADH + CO₂; key TCA regulatory point; inhibited by ATP, activated by ADP and Ca²⁺.

α-Ketoglutarate Dehydrogenase

Converts α-ketoglutarate → succinyl-CoA + NADH + CO₂; inhibited by NADH and succinyl-CoA; activated by Ca²⁺; exergonic, helps set TCA flux.

TCA Energy Yield per Acetyl-CoA

3 NADH → ~7.5 ATP, 1 FADH₂ → ~1.5 ATP, 1 GTP → 1 ATP, 2 CO₂ released; majority of energy conserved via electrons to ETC.

PDH Regulation – Allosteric

Inhibited by ATP, NADH, acetyl-CoA; activated by AMP, CoA, NAD⁺, Ca²⁺; integrates energy status with acetyl-CoA production.

PDH Regulation – Covalent

PDH kinase phosphorylates → inactivates; PDH phosphatase dephosphorylates → activates; modulated by ATP, NADH, acetyl-CoA, ADP, pyruvate, NAD⁺, CoA, Ca²⁺, insulin.

Metabolic Commitment by PDH

PDH links glycolysis to TCA cycle; committing pyruvate to acetyl-CoA integrates carbohydrate metabolism with energy production and biosynthesis.

Substrate Channeling in PDH and TCA

Intermediates are passed directly between enzyme active sites (e.g., lipoyl arm in PDH, metabolons in TCA) to increase efficiency and prevent side reactions.

Moonlighting Proteins in Metabolism

Single proteins can have multiple functions, e.g., cytosolic aconitase/IRP1 regulates both NADPH production and iron homeostasis; illustrates integration of metabolic and regulatory networks.

Tumor Cell CAC Alterations

MPC down-regulated → cytosolic pyruvate accumulates; PDH and SDH often inactivated → lactate and succinate accumulate → oncometabolites; illustrates metabolic rewiring.