TCA Cycle

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  • 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