Citric Acid Cycle

The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. The TCA cycle oxidizes acetyl-CoA and produces 2 CO2, GTP, 3 NADH + H+, and FADH2. Its end products (NADH + H+ and FADH2) are passed into the electron transport chain to yield a total of 10 ATP per cycle.

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Production of energy 

  • Direct production of guanosine triphosphate (GTP) (equivalent to adenosine triphosphate [ATP])
  • NADH + H+ and FADH2 then produce ATP within the respiratory chain. 

Amphibolic center

The citric acid cycle provides precursors for many catabolic and anabolic processes.

  • Precursors for amino acids: 
    • Alpha-ketoglutarate for glutamate
    • Oxaloacetate for aspartate
  • Succinyl-CoA is crucial for the synthesis of porphyrins or heme.
  • Citrate is needed for the synthesis of fatty acids and cholesterol.
  • Oxaloacetate is a substrate for gluconeogenesis.

Reactions, Yield, and Energy Balance

Schematic diagram of the citric acid cycle

Image by Lecturio.

Two main substrates: acetyl-CoA and oxaloacetate

  • Acetyl-CoA from the beta-oxidation of fatty acids and glycolysis 
    • Pyruvate dehydrogenase produces acetyl-CoA from pyruvate.
  • Oxaloacetate from regeneration within the Krebs cycle or from pyruvate
    • Pyruvate carboxylase produces oxaloacetate from pyruvate and CO2.

Acetyl-CoA (C2) + oxaloacetate (C4) → Citrate (C6) → Isocitrate (C6) → α-Ketoglutarate (C5) → Succinyl-CoA (C4) → Succinate (C4) → Fumarate (C4) → Malate (C4) → Oxaloacetate (C4)
Mnemonic device: Citrate Is Krebs’ Starting Substrate For Making Oxaloacetate

Notable reactions:

  • Irreversible:
    • Acetyl-CoA + oxaloacetate → citrate via citrate synthase
    • Isocitrate → α-ketoglutarate via isocitrate dehydrogenase
    • α-ketoglutarate → succinyl-CoA via α-ketoglutarate dehydrogenase
  • Succinate dehydrogenase: only enzyme of the Krebs cycle that is anchored to the inner membrane of the mitochondrion
  • α-ketoglutarate dehydrogenase: requires 5 cofactors (thiamine pyrophosphate, lipoic acid, coenzyme A, FAD, and NAD+)

3 NADH + H+ + 1 FADH2 + 1 GTP + 2 CO2 per acetyl-CoA (x 2 per glucose)

Energy balance:
7,5 ATP (3 NADH + H+) + 1,5 ATP (1 FADH2) + 1 ATP (1 GTP) = 10 ATP per acetyl-CoA (x 2 per glucose)


Regulation of the citric acid cycle
(mainly by the availability of substrates and product inhibition)
EnzymeActivation byInhibition by
Pyruvate dehydrogenase
  • ADP
  • Low NADH/NAD+ ratio
  • Ca2+
  • High acetyl-CoA/CoA ratio
  • High NADH/NAD+ ratio
  • High ATP/ADP ratio
Citrate synthase
  • ADP
  • Oxaloacetate
  • Acetyl-CoA
  • Citrate
  • NADH + H+
  • ATP
  • Succinyl-CoA
Isocitrate dehydrogenase (biggest impact on the citric acid cycle)
  • ADP
  • Ca2+
  • ATP
  • NADH + H+
α-ketoglutarate dehydrogenaseCa2+
  • Succinyl-CoA
  • NADH + H+
Succinate dehydrogenaseSuccinateOxaloacetate

Clinical Relevance

The following process is stimulated by the tricarboxylic acid (TCA) cycle:

  • Ketogenesis: the synthesis of ketone bodies from acetyl-CoA. Ketogenesis is caused by prolonged starvation, diabetic ketoacidosis, and alcoholism. The inhibition of the TCA cycle leads to a rise in acetyl-CoA levels, which directly stimulates ketogenesis.

The following conditions inhibit the TCA cycle:

  • Hyperammonemia: a condition defined by an excess of ammonia in the blood. It may be acquired (liver disease) or hereditary (urea cycle enzyme deficiencies). In hyperammonemia, the level of α-ketoglutarate rises, inhibiting the TCA cycle. It presents as asterixis, slurring of speech, somnolence, vomiting, cerebral edema, and blurry vision. 
  • Thiamine deficiency: a condition that occurs due to malnutrition and/or alcoholism, which inhibits the enzyme α-ketoglutarate dehydrogenase via a lack of one of its cofactors (thiamine). This leads to the accumulation of glutamate, leading to Wernicke’s encephalopathy. It presents as a triad of confusion, ophthalmoplegia, and ataxia.
  • Diabetic ketoacidosis: a condition primarily seen in patients with type I diabetes mellitus, which is caused by insufficient insulin levels. It presents with hyperglycemia, polyuria, polydipsia, nausea, vomiting, and volume depletion. It can inhibit the TCA cycle by lowering the levels of oxaloacetate.
  • Alcohol use disorder: Alcoholism is a level of alcohol consumption that exceeds the sociocultural standard. The condition is marked by mental and physical addiction with an irresistible desire for alcohol and tolerance of the drug. It can inhibit the TCA cycle by causing a rise in the NADH/NAD+ ratio.
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