TCA Cycle

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