The citric acid cycle, also known as the Krebs cycle or TCA cycle, is the central hub of cellular metabolism. It takes place in the mitochondrial matrix and completes the oxidation of carbohydrates, fats, and proteins by converting acetyl-CoA into carbon dioxide.

How the Citric Acid Cycle Works

1. Entry: Citrate Formation

Acetyl-CoA (derived from pyruvate, fatty acids, or amino acids) combines with oxaloacetate, a four-carbon molecule, to form citrate, a six-carbon molecule. This reaction is catalyzed by citrate synthase and is essentially irreversible.

2. Isomerization and First Oxidation

Citrate is isomerized to isocitrate via the intermediate cis-aconitate. Isocitrate is then oxidized by isocitrate dehydrogenase, releasing the first molecule of CO2 and producing NADH. The product is alpha-ketoglutarate, a five-carbon molecule.

3. Second Oxidation

Alpha-ketoglutarate is oxidized by alpha-ketoglutarate dehydrogenase, releasing a second CO2 and producing NADH. This reaction is similar to the pyruvate dehydrogenase reaction and produces succinyl-CoA.

4. Substrate-Level Phosphorylation

Succinyl-CoA is converted to succinate by succinyl-CoA synthetase. This reaction produces GTP (or ATP in some organisms) through substrate-level phosphorylation—the only direct ATP-producing step of the cycle.

5. Regeneration of Oxaloacetate

Succinate is oxidized to fumarate by succinate dehydrogenase, producing FADH2. Fumarate is then hydrated to malate, and malate is oxidized to oxaloacetate by malate dehydrogenase, producing another NADH. The regenerated oxaloacetate is ready to combine with another acetyl-CoA.

6. Net Yield per Turn

Each turn of the cycle produces:

• 3 NADH
• 1 FADH2
• 1 GTP (or ATP)
• 2 CO2