Medicine & USMLE

Citric Acid Cycle (TCA, Krebs)

  1. Citric Acid Cycle (TCA, Krebs)
  2. Glycolysis - Investment Phase
  3. Glycolysis - Payoff Phase
  4. Pentose Phosphate Pathway - Oxidative Phase
  5. Pentose Phosphate Pathway - Non-Oxidative Phase
  6. Glycogenesis
  7. Glycogenolysis
  8. Gluconeogenesis
  9. Electron Transport Chain (ETC)


The Citric Acid cycle begins with acetyl-CoA and oxaloacetate, which are converted to citrate by citrate synthase. This step is irreversible and is hence a site of regulation.

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

Isocitrate dehydrogenase next catalyzes the formation of alpha-ketoglutarate, NADH, and CO2. This step is also irreversible and is therefore a regulatory step.

Alpha-Ketoglutarate dehydrogenase next catalyzes the formation of succinyl-CoA, NADH, and CO2. This step is also irreversible and is hence regulated.

Next, Succinyl-CoA synthetase catalyzes the conversion of succinyl-CoA to Succinate, meanwhile forming GTP.

In the next step, Succinate dehydrogenase converts succinate to fumarate, meanwhile generating FADH2.

Next, fumarase converts fumarate to malate.

Finally, Malate dehydrogenase reforms oxaloacetate, meanwhile generating NADH. Oxaloacetate can then be reintegrated into the cycle, which repeats.

Key Points

  • TCA cycle
    • Etymology
      • Citrate has 3 carboxylic acid groups (TCA cycle =TriCarboxylic Acid cycle)
      • Also called Krebs cycle or Citric Acid cycle
        • Discovered by Hans Krebs (Krebs cycle)
        • 1st step produces citrate (citric acid cycle)
    • Summary
      • TCA cycle is a metabolic pathway that metabolizes biomolecules to produce high energy products
        • High energy products: NADH, FADH2, and GTP
          • NADH and FADH2 are used to produced ATP in the Electron Transport Chain
          • GTP can be converted to ATP at no energy cost
      • Central hub
        • Protein, Carbs, and Fats can be all metabolized and fed into the TCA for energy production
        • Starting molecule: acetyl-CoA
          • Can be produced from pyruvate (final product of carbohydrate metabolism)
          • Can also be produced from the metabolism of fats and proteins
      • Produces CO2
        • Carbons from acetyl-CoA are oxidized to CO2
          • Allows for energy payoff as high energy products
          • The Carbons that are oxidized in a given cycle actually come from oxaloacetate. However, the carbons from acetyl-CoA get integrated into oxaloacetate and are then oxidized over the course of a few rounds of the TCA cycle
      • Overall reaction: Acetyl-CoA + 3NAD+ + FAD + GDP + Pi +2H2O → 2CO2 + CoA-SH + 3NADH + 3H+ + FADH2 + GTP
    • Location
      • Occurs in the mitochondrial matrix
        • Part of aerobic respiration, coupled with oxidative phosphorylation 
          • Inhibited in anaerobic conditions
    • Reaction steps
      • oxaloacetate + acetyl-CoA →[citrate synthase]  citrate
        • Irreversible (regulatory site)
          • Acetyl group is linked to CoA by a high energy thioester bond
            • Breaking that bond is very exergonic, making the overall delta G very negative
              • Oxaloacetate is normally present at low concentrations, so this negative delta G helps drag the reaction forward
            • Thioesters may have played the role of ATP in the primordial stages of life’s development
      • citrate → [aconitase] isocitrate
        • Intermediate: cis-aconitate
      • isocitrate → [isocitrate dehydrogenase] alpha-ketoglutarate
        • Produces 1 NADH and 1 CO2
        • Irreversible (regulatory site)
      • alpha-ketoglutarate → [alpha-ketoglutarate dehydrogenase] succinyl-CoA
        • succinyl-CoA linked by high energy thioester bond
          • Some of the energy from oxidizing carbon is preserved in this bond
            • This energy is used to power GTP production in the next step
        • Produces 1 NADH and 1 CO2
        • Irreversible (regulatory site)
      • succinyl-CoA → [succinyl-CoA synthetase] succinate
        • Produces 1 GTP
          • 1 GTP = 1 ATP
      • succinate → [succinate dehydrogenase] fumarate
        • Produces 1 FADH2 
      • fumarate → [fumarase] malate 
      • malate → [malate dehydrogenase] oxaloacetate
        • Produces 1 NADH
        • Oxaloacetate can then recycle back into the first step of the cycle: Acetyl-CoA + oxaloacetate → citrate
          • Cycle repeats
    • Regulation
      • Regulation is based on the energy needs of the cell
      • TCA cycle is primarily regulated allosterically at the irreversible steps
      • TCA slows down (inhibition)
        • Downregulated by molecules that are present at higher concentrations when the cell has plenty of energy
          • NADH, ATP and other products of the pathway 
      • TCA speeds up (activation)
        • Upregulated by molecules/ions that are present at higher concentrations when the cell needs more energy
          • ADP, NAD+
            • Might be framed as a high ADP/ATP and high NAD+/NADH ratio
          • Ca2+
            • Ca2+ causes muscle contraction and a contracting muscle requires energy, so Ca2+ upregulates TCA cycle