Citric acid cycle

Last revised by Frank Gaillard on 17 May 2024

The citric acid cycle, also known as the Krebs cycle or tricarboxylic acid cycle, is a central metabolic pathway in cells. It involves a series of chemical reactions that oxidize acetyl-CoA derived from carbohydrates, fats, and proteins to produce energy in the form of ATP and electron carriers (NADH and FADH2) and release carbon dioxide.

This cycle takes place within the mitochondria of eukaryotic cells and is a critical step in aerobic respiration.

The reason it is a cycle is that the series of metabolic steps is perpetual, recycling the end product (oxaloacetate) by combining it with acetyl-CoA to begin the cycle again.

Metabolic steps

  1. acetyl-CoA entry: acetyl-CoA, derived from the breakdown of carbohydrates, fats, or proteins, enters the cycle and is combined with oxaloacetate to form citrate in a reaction catalyzed by the enzyme citrate synthase.

  2. isomerization: citrate is converted to isocitrate by the enzyme aconitase.

  3. first oxidation: isocitrate is oxidized to alpha-ketoglutarate with the production of NADH and the release of carbon dioxide (CO2). This reaction is catalyzed by isocitrate dehydrogenase (IDH 2 and 3).

  4. second oxidation: alpha-ketoglutarate is further oxidized to succinyl-CoA, releasing NADH and CO2. This reaction is catalyzed by alpha-ketoglutarate dehydrogenase complex.

  5. substrate-level phosphorylation: succinyl-CoA is converted to succinate, and in the process, a molecule of GTP is generated which in turn results in the phosphorylation of ADP into ATP the primary energy molecule of human metabolism. This step is catalyzed by succinyl-CoA synthetase.

  6. third oxidation: succinate is oxidized to fumarate, producing FADH2, in a reaction catalyzed by succinate dehydrogenase, which is unique as it is embedded in the inner mitochondrial membrane and also participates in the electron transport chain.

  7. hydration: fumarate is converted to malate via the addition of water. The enzyme responsible for this step is fumarase.

  8. fourth oxidation: malate is oxidized to regenerate oxaloacetate, releasing NADH in the process. This reaction is catalyzed by malate dehydrogenase.

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