TCA Cycle

TCA Cycle (Krebs / Citric Acid Cycle)

The TCA cycle is a circular series of 8 reactions occurring in the mitochondrial matrix. It is the final common pathway for the oxidation of carbohydrates, fats, and amino acids. Each turn completely oxidizes one acetyl group (2 carbons) to 2 CO₂.

Entry Point

Acetyl-CoA (2C) condenses with Oxaloacetate (4C) to form Citrate (6C) — catalyzed by Citrate Synthase. The 2 carbons from acetyl-CoA are not lost until the 2nd turn (equivalent carbons are released as CO₂).

8 Steps of TCA Cycle

  1. Citrate Synthase: OAA + Acetyl-CoA → Citrate (irreversible; inhibited by NADH, succinyl-CoA, ATP)
  2. Aconitase: Citrate → Isocitrate (via cis-Aconitate); inhibited by fluoroacetate
  3. Isocitrate Dehydrogenase: Isocitrate → α-Ketoglutarate + CO₂ + NADH (rate-limiting step; activated by ADP; inhibited by NADH, ATP)
  4. α-Ketoglutarate Dehydrogenase: α-KG → Succinyl-CoA + CO₂ + NADH (requires TPP, FAD, NAD+, CoA, lipoic acid — same as PDC)
  5. Succinyl-CoA Synthetase: Succinyl-CoA → Succinate + GTP (only substrate-level phosphorylation in TCA)
  6. Succinate Dehydrogenase: Succinate → Fumarate + FADH₂ (Complex II of ETC; inhibited by malonate)
  7. Fumarase: Fumarate → Malate (hydration)
  8. Malate Dehydrogenase: Malate → Oxaloacetate + NADH (regenerates OAA to continue cycle)

Energy Yield per Acetyl-CoA

  • 3 NADH → 7.5 ATP (via ETC)
  • 1 FADH₂ → 1.5 ATP (via ETC)
  • 1 GTP → 1 ATP
  • Total: ~10 ATP per acetyl-CoA
  • Per glucose (2 acetyl-CoA): ~20 ATP from TCA alone

Amphibolic Nature

TCA is amphibolic — serves both catabolism AND anabolism. Intermediates are withdrawn (cataplerosis) for biosynthesis: α-KG → glutamate/GABA; OAA → aspartate/glucose; Succinyl-CoA → heme synthesis; Citrate → fatty acid synthesis (exits mitochondria).

Anaplerotic Reactions (refilling TCA)

  • Pyruvate Carboxylase: Pyruvate + CO₂ → OAA (activated by Acetyl-CoA; requires Biotin). Major anaplerotic reaction in liver.
  • Amino acid catabolism → α-KG, OAA, succinyl-CoA, fumarate, malate
  • Propionyl-CoA (odd-chain FA) → Succinyl-CoA

Regulation

TCA is regulated by: substrate availability, product inhibition (NADH, ATP inhibit key enzymes), and calcium (activates isocitrate dehydrogenase, α-KGDH, and PDC in muscle — coupling contraction with energy production).