Metabolism

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