Acetyl-CoA to Citrate: Carbon Counting in the Krebs Cycle for the MCAT

Carbon counting is one of the most reliable ways to keep the citric acid cycle straight. The cycle is a loop, so what matters is what enters, what leaves, and what is regenerated.

Entry: acetyl-CoA plus oxaloacetate

Citrate synthase joins acetyl-CoA (2 carbons) to oxaloacetate (4 carbons) to make citrate, which has 6 carbons. The CoA is released. Because citrate synthase is highly exergonic, this step helps pull the cycle forward.

Acetyl-CoA comes from pyruvate by the pyruvate dehydrogenase complex, which also releases one CO₂ and makes one NADH per pyruvate (3 carbons to 2).

Carbon tally through one turn

Two carbons enter as acetyl-CoA and two leave as CO₂, but they are not the same two atoms. The CO₂ released in a turn comes from the oxaloacetate-derived carbons, and the acetyl carbons are lost in later turns.

Per acetyl-CoA and per glucose

• Per turn (one acetyl-CoA): 3 NADH, 1 FADH₂, 1 GTP or ATP, and 2 CO₂.
• Per glucose: one glucose gives two pyruvate, so two acetyl-CoA, so the cycle turns twice. Double the numbers: 6 NADH, 2 FADH₂, 2 GTP or ATP, and 4 CO₂ from the cycle itself.
• Including pyruvate dehydrogenase, a glucose releases 6 CO₂ in total.

Where the cycle is regulated

Isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase are inhibited by NADH and ATP, and citrate synthase is inhibited by its product citrate and by ATP. High ADP activates isocitrate dehydrogenase.

Common traps

• Saying 2 acetyl-CoA enter per turn. One enters per turn; two per glucose.
• Counting the carbons wrong in citrate. It is 6, not 4 or 2.
• Treating the cycle as direct ATP production. Most energy leaves as NADH and FADH₂.
• Forgetting the link step. PDH is separate from the cycle.

One-minute recap

• Acetyl-CoA (2C) plus oxaloacetate (4C) gives citrate (6C).
• Two CO₂ leave per turn, at isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase.
• Per glucose, the cycle turns twice.