The citric acid cycle, also called the Krebs cycle or tricarboxylic acid (TCA) cycle, is the central metabolic pathway that provides most of the cell’s energy. It takes place in the mitochondrial matrix and plays a major role in oxidizing carbohydrates, fats, and amino acids to produce ATP.
About 65–70% of the ATP in the body is produced through oxidative phosphorylation, and nearly 10% of that originates directly from reactions linked to the Krebs cycle. The cycle also uses almost two-thirds of the total oxygen consumed by the body.
Hans Adolf Krebs proposed this cycle in 1937 based on experiments involving oxygen consumption in pigeon breast muscle. The pathway is common to carbohydrates, lipids, and proteins because they all form acetyl-CoA, the molecule that enters the TCA cycle.
Steps of the Citric Acid Cycle
1. Formation of Citrate
Acetyl-CoA combines with oxaloacetate to form citrate.
Enzyme: Citrate synthase.
This step controls the rate of the cycle because citrate synthase initiates the entry of acetyl units into the pathway. Citrate can also inhibit citrate synthase, helping regulate its own formation. This reaction links carbohydrate, fat, and protein metabolism since all three produce acetyl-CoA.
2. Isomerization of Citrate to Isocitrate
Citrate is converted to isocitrate through dehydration and rehydration.
Enzyme: Aconitase.
Aconitase rearranges citrate into a form suitable for oxidation. This reversible step prepares the molecule for the first decarboxylation of the cycle.
3. Formation of α-Ketoglutarate
Isocitrate undergoes oxidative decarboxylation to form α-ketoglutarate, NADH, and CO₂.
Enzyme: Isocitrate dehydrogenase (ICD).
This is a key regulatory step. It produces NADH and releases CO₂. α-Ketoglutarate is a central molecule used in amino acid synthesis, especially in forming glutamate.
4. Conversion of α-Ketoglutarate to Succinyl-CoA
α-Ketoglutarate is oxidatively decarboxylated to succinyl-CoA, producing NADH and CO₂.
Enzyme: α-Ketoglutarate dehydrogenase complex.
This enzyme requires several cofactors: TPP, lipoamide, NAD⁺, FAD, and CoA. The reaction is similar to the pyruvate dehydrogenase complex and is another important regulatory point in the cycle.
5. Formation of Succinate
Succinyl-CoA is converted to succinate, producing GTP or ATP through substrate-level phosphorylation.
Enzyme: Succinyl-CoA synthetase.
This is the only step in the cycle that directly generates a high-energy phosphate (GTP or ATP). It also allows succinyl-CoA to continue into later steps of the cycle.
6. Conversion of Succinate to Fumarate
Succinate is oxidized to fumarate, forming FADH₂.
Enzyme: Succinate dehydrogenase.
This enzyme is unique because it is part of both the TCA cycle and the electron transport chain. The FADH₂ produced transfers its electrons directly to the respiratory chain.
7. Formation of Malate
Fumarate is hydrated to form malate.
Enzyme: Fumarase.
Water is added to fumarate to produce malate, preparing it for the final oxidation step in the cycle.
8. Regeneration of Oxaloacetate
Malate is oxidized to oxaloacetate, producing NADH.
Enzyme: Malate dehydrogenase.
Oxaloacetate is regenerated to combine again with acetyl-CoA and continue the cycle. This step ensures a continuous flow of carbon and electron carriers for ATP synthesis.
Energetics of the Citric Acid Cycle
During the oxidation of one acetyl-CoA molecule, the cycle produces:
- 3 NADH
- 1 FADH₂
- 1 GTP/ATP
- 2 CO₂
Energy yield:
- 3 NADH → 9 ATP (via electron transport chain)
- 1 FADH₂ → 2 ATP
- 1 GTP/ATP → 1 ATP
Total ATP per acetyl-CoA: 12 ATP
Enzymes of the Citric Acid Cycle
- Citrate synthase
- Aconitase
- Isocitrate dehydrogenase
- α-Ketoglutarate dehydrogenase
- Succinyl-CoA synthetase
- Succinate dehydrogenase
- Fumarase
- Malate dehydrogenase
Regulation of the Citric Acid Cycle
Citrate Synthase
Inhibited by ATP, NADH, acetyl-CoA, and succinyl-CoA.
Isocitrate Dehydrogenase
Activated by ADP.
Inhibited by ATP and NADH.
α-Ketoglutarate Dehydrogenase
Activated by ADP.
Inhibited by NADH and succinyl-CoA.
Importance of ADP
ADP levels control how fast oxidative phosphorylation occurs. Low ADP slows NADH and FADH₂ oxidation, which slows the entire TCA cycle. Adequate ADP ensures smooth electron flow and sustained ATP formation.
The citric acid cycle is the central pathway of energy production. It generates ATP, NADH, and FADH₂ for oxidative phosphorylation. Proper regulation of its enzymes maintains efficient energy flow and metabolic balance in the cell.
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