The Krebs cycle
Tricarboxylic acid cycle: stoichiometry, thermodynamics, and control
1. Location and function
An amphibolic pathway in the mitochondrial matrix that oxidizes acetyl-CoA (from PDH, β-oxidation, and amino acid catabolism) to 2 CO₂ and transfers 8 e⁻ to 3 NAD⁺ and 1 FAD. Topological exception: succinate dehydrogenase sits in the inner membrane as complex II.
It doesn't consume O₂ directly, but it's strictly aerobic: without the respiratory chain, NADH and FADH₂ aren't reoxidized, available NAD⁺ drops, and the flux stops.
2. Reactions
- Citrate synthase: acetyl-CoA + OAA + H₂O → citrate + CoA-SH ΔG°′ −32 kJ/mol
- Aconitase (Fe-S center): citrate ⇌ isocitrate, via cis-aconitate
- Isocitrate DH: → α-ketoglutarate + CO₂ + NADH −8
- α-KG DH complex (TPP, lipoate, CoA, FAD, NAD⁺): → succinyl-CoA + CO₂ + NADH −33
- Succinyl-CoA synthetase: → succinate + GTP; substrate-level phosphorylation
- Succinate DH (FAD): → fumarate + FADH₂; competitively inhibited by malonate
- Fumarase: fumarate + H₂O → L-malate (stereospecific)
- Malate DH: → OAA + NADH +30; it runs forward because citrate synthase keeps OAA very low
3. Net yield
Per turn: 3 NADH + 1 FADH₂ + 1 GTP + 2 CO₂. With P/O ratios of 2.5 and 1.5, that works out to ≈ 10 ATP per acetyl-CoA (×2 per glucose).
4. Control
Three irreversible steps: citrate synthase (− citrate, succinyl-CoA, NADH, ATP), isocitrate DH (+ ADP, Ca²⁺; − ATP, NADH) and α-KG DH (+ Ca²⁺; − succinyl-CoA, NADH). The dominant signal is the NADH/NAD⁺ ratio.

