Medicine & USMLE

Citric Acid Cycle (TCA Cycle)

Biochemical Pathways
  1. Glycolysis
  2. Citric Acid Cycle (TCA Cycle)
  3. Electron Transport Chain (ETC)
  4. Cori Cycle
  5. De Novo Purine Synthesis
  6. De Novo Pyrimidine Synthesis
  7. Purine Salvage
  8. Purine Excretion
  9. Ethanol Metabolism
  10. Pyruvate Metabolism
  11. HMP Shunt (Pentose Phosphate Pathway)
  12. Galactose Metabolism
  13. Sorbitol (Polyol) Pathway
  14. Urea Cycle
  15. Alanine (Cahill) Cycle
  16. Catecholamine Synthesis & Breakdown
  17. Homocysteine Metabolism
  18. Fatty Acid Synthesis (Citrate Shuttle)
  19. Fatty Acid Breakdown (Carnitine Shuttle)
  20. Propionic Acid Pathway
  21. Fructose Metabolism
  22. Regulation by Fructose-2,6-Bisphosphate (F-2,6-BP)
  23. Glycogenesis
  24. Glycogenolysis


The Citric Acid cycle, also known as the Krebs cycle or tricarboxylic acid (TCA) cycle, is a biochemical pathway that plays a central role in cellular respiration.

Although many biomolecules like fats, proteins, and others can be broken down to enter this cycle, the classic metabolite is pyruvate derived from glycolysis.  Pyruvate must first be converted into acetyl-CoA, by the pyruvate dehydrogenase complex, in a reaction that requires 5 cofactors, including Vitamin B1 AKA thiamine, Vitamin B2 AKA riboflavin, Vitamin B3 AKA niacin, Vitamin B5 AKA pantothenic acid, as well as lipoic acid. This pyruvate dehydrogenase complex also produces 1 molecule of NADH and carbon dioxide. This step is irreversible and is a site of regulation.

Acetyl-CoA is the actual starter molecule that enters the citric acid cycle. Acetyl-CoA combines with oxaloacetate to form citrate, in a reaction that is catalyzed by citrate synthase. This step is irreversible and is hence a site of regulation.

Next, aconitase catalyzes the conversion of Citrate to cis-aconitate, and then quickly to Isocitrate.

Isocitrate dehydrogenase then catalyzes the formation of alpha-ketoglutarate from isocitrate, producing 1 molecule of NADH and carbon dioxide in the process. This step is also irreversible and is therefore a regulatory step. Notably, isocitrate dehydrogenase is inhibited by high levels of ammonia.

Afterwards, the alpha-ketoglutarate is converted into succinyl-CoA in a reaction catalyzed by  alpha-ketoglutarate dehydrogenase. Alpha-ketoglutarate dehydrogenase is a complex that requires the same 5 factors as pyruvate dehydrogenase complex: namely, vitamin B1, B2, B3, B5, and lipoic acid. This reaction also produces 1 molecule of NADH and carbon dioxide. This step is also irreversible and is regulated.

Next, Succinyl-CoA is converted into Succinate, forming 1 molecule of GTP and releasing CoA in the process.

In the next step, Succinate dehydrogenase converts succinate to fumarate, generating 1 molecule of FADH2 in the process.

Next, fumarase converts fumarate to malate.

Finally, Malate dehydrogenase reforms oxaloacetate from malate, generating 1 molecule of NADH in the process. Oxaloacetate can then be reused in the cycle by combining with another molecule of acetyl-CoA.

In total, the citric acid cycle produces 3 molecules of NADH, 1 molecule of FADH2, and 1 molecule of GTP per unit of acetyl-CoA that enters. If we account for pyruvate as the starting point before acetyl-CoA, this adds 1 more molecule of NADH produced. These electron carriers then feed their electrons into the electron transport chain, which ultimately generates ATP via oxidative phosphorylation. Since the citric acid cycle is coupled to oxidative phosphorylation -- and hence oxygen -- the pathway is inhibited in anaerobic environments. This makes this cycle an important part of aerobic metabolism.

Key Points

  • Citric Acid Cycle
    • Other names
      • Krebs Cycle
        • Named after the scientist who discovered the pathway, Sir Hans Krebs
      • Tricarboxylic Acid (TCA) Cycle
        • Since citric acid (citrate), the first intermediate in this cycle has 3 carboxylic acid groups, it is a tricarboxylic acid
    • Function
      • Generates high-energy molecules from Acetyl-CoA
        • Produces 3 NADH, 1 FADH2, 2 CO2, 1 GTP per Acetyl-CoA
        • Including pyruvate, this is 4 NADH
        • After undergoing the electron transport chain, this generates ~10 ATP per molecule of Acetyl-CoA
      • All reactions occur in the mitochondria
    • Pathway
      • Pyruvate (3C) → Acetyl-CoA (2C)
        • Produces NADH + CO2
          • 1 carbon from pyruvate is converted into CO2
        • Catalyzed by Pyruvate Dehydrogenase Complex (irreversible)
          • Requires 5 cofactors: B1, B2, B3, B5, lipoic acid
        • Inhibited by ATP, Acetyl-CoA, NADH
      • Acetyl-CoA (2C) + Oxaloacetate (4C) → Citrate (6C)
        • Catalyzed by citrate synthase (irreversible)
        • Inhibited by ATP
      • Citrate (6C) → Isocitrate (6C)
        • Via cis-Aconitate, in a reaction catalyzed by Aconitase
      • Isocitrate (6C) → alpha-ketoglutarate (5C)
        • Via isocitrate dehydrogenase (irreversible)
        • Produces NADH + CO2
          • 1 carbon from isocitrate is converted into CO2
        • Reaction is blocked by high levels of ammonia
          • Thought to be cause of encephalopathy in hyperammonemia, e.g. liver failure
        • Inhibited by ATP and NADH
        • Stimulated by ADP
      • alpha-ketoglutarate (5C) → Succinyl-CoA (4C)
        • Via alpha-ketoglutarate dehydrogenase (irreversible)
          • Requires same 5 cofactors as pyruvate dehydrogenase complex (B1, B2, B3, B5, lipoic acid)
        • Produces NADH + CO2
          • 1 carbon from alpha-ketoglutarate is converted into CO2
        • Inhibited by Succinyl-CoA, NADH, ATP
      • Succinyl-CoA (4C) → Succinate (4C)
        • Via succinate thiokinase/succinate-CoA synthetase (reversible)
        • Produces GTP + CoA
      • Succinate (4C) → Fumarate (4C)
        • Via succinate dehydrogenase (reversible)
          • Derived from Vitamin B2 (FAD)
          • Same reaction as ETC, but in reverse
        • Produces FADH2
      • Fumarate (4C) → Malate (4C)
        • Via fumarase (reversible)
      • Malate (4C) → Oxaloacetate (4C)
        • Via malate dehydrogenase (reversible)
        • Produces NADH
          • Excess NADH may inhibit this reaction
        • Oxaloacetate repeats cycle