Reactions of the Citric Acid Cycle
High-Yield Summary
- The citric acid cycle (TCA cycle) runs in the mitochondrial matrix. Its job is oxidizing carbon, not directly making ATP — the payoff is NADH/FADH₂ that later drive the ETC.
- 8 steps per turn, starting when acetyl-CoA's 2-carbon group joins oxaloacetate to form citrate; oxaloacetate is regenerated at the end.
- Net yield per turn (1 acetyl-CoA): 3 NADH, 1 FADH₂, 1 GTP, 2 CO2.
- Isocitrate dehydrogenase is the rate-limiting step. Succinate dehydrogenase = Complex II of the ETC (only step producing FADH₂, embedded in the inner mitochondrial membrane).
- Per pyruvate (PDC + 1 turn): 4 NADH + 1 FADH₂ + 1 GTP = 12.5 ATP. Per glucose (2 pyruvate): 25 ATP from this stage alone.
- 3 regulatory control points — citrate synthase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase — all inhibited by high ATP/NADH, activated by low-energy signals (ADP, NAD⁺, calcium).
Key Terms
- Oxaloacetate
- 4-carbon acceptor molecule that combines with acetyl-CoA to start the cycle and is regenerated at the end.
- Substrate-level phosphorylation
- Direct GTP formation at the succinyl-CoA synthetase step — the cycle's only direct high-energy phosphate product.
- Complex II
- Succinate dehydrogenase — the only citric acid cycle enzyme embedded in the inner mitochondrial membrane, also part of the ETC.
The 8 Steps
- 1Citrate synthase: acetyl-CoA + oxaloacetate → citrate (CoA released; strongly favorable, pulls the cycle forward)
- 2Aconitase: citrate → isocitrate (via cis-aconitate)
- 3Isocitrate dehydrogenase (rate-limiting): isocitrate → alpha-ketoglutarate (1st NADH, 1st CO2)
- 4Alpha-ketoglutarate dehydrogenase: → succinyl-CoA (2nd NADH, 2nd CO2)
- 5Succinyl-CoA synthetase: → succinate (substrate-level phosphorylation → GTP)
- 6Succinate dehydrogenase (= Complex II): → fumarate (FADH₂, only FADH₂-producing step)
- 7Fumarase: → malate (hydration)
- 8Malate dehydrogenase: → oxaloacetate (3rd/final NADH; pulled forward by citrate synthase consuming oxaloacetate)
Yield Per Turn and Per Glucose
1 acetyl-CoA → 3 NADH + 1 FADH₂ + 1 GTP + 2 CO2
- Per pyruvate = PDC (1 NADH) + 1 turn (3 NADH, 1 FADH₂, 1 GTP) = 4 NADH + 1 FADH₂ + 1 GTP ≈ 12.5 ATP
- Per glucose = 2 pyruvate → 2 turns ≈ 25 ATP from PDC + TCA combined
- MCAT conventions: NADH ≈ 2.5 ATP, FADH₂ ≈ 1.5 ATP, GTP = 1 ATP.
- ATP from NADH/FADH₂ is realized later at the ETC, not during the cycle itself.
Three Regulatory Control Points
| Enzyme | Inhibited by / Activated by |
|---|---|
| Citrate synthase | Inhibited: ATP, NADH, succinyl-CoA, citrate |
| Isocitrate dehydrogenase | Inhibited: ATP, NADH / Activated: ADP, NAD⁺ |
| Alpha-ketoglutarate dehydrogenase | Inhibited: ATP, NADH, succinyl-CoA / Activated: ADP, calcium |
Common MCAT Trap
- The cycle's ATP payoff comes mostly from NADH/FADH₂ feeding the ETC afterward, not from the cycle's own single GTP — don't equate 'citric acid cycle' with 'direct ATP production.'
- Succinate dehydrogenase (Complex II) is the only TCA enzyme embedded in the inner mitochondrial membrane — every other TCA enzyme is soluble in the matrix.
- Isocitrate dehydrogenase, not citrate synthase, is the rate-limiting step — a frequent mix-up.
Quick Recall
What is the rate-limiting enzyme of the citric acid cycle?
Which step produces FADH₂, and what is unique about that enzyme?
What is the net yield of one turn of the cycle?
What's the total ATP yield per glucose from PDC + TCA combined?