Citric Acid Cycle and its Regulation

May 20, 2024

Lecture Notes: Citric Acid Cycle Regulation

Overview of the Citric Acid Cycle (CAC)

  • Begins with: Acetyl CoA combining with oxaloacetate to form citrate.
  • Acetyl CoA: Two carbon molecule.
  • Key Outputs: Acetyl CoA is oxidized and exits as CO2; production of NADH, FADH2, and GTP.

Overall Chemical Reaction of CAC

  • Reactants: Acetyl CoA, NAD+, FAD, GDP.
  • Products: CO2, NADH, FADH2, GTP.
  • Importance: NADH and FADH2 go to the electron transport chain for ATP production.

Difference from Glycolysis

  • Glycolysis: Can be turned on/off based on glucose availability.
  • CAC: Always on but at varying speeds to meet energy needs of the cell.

Modes of CAC Regulation

  1. Allosteric Regulation
  • Definition: Molecules bind to enzymes at non-active sites causing conformational changes.
  • Types: Allosteric activators or inhibitors based on the effect on enzyme activity.
  • Response: Adjusts to the energy needs of the cell.
  1. Substrate Availability
  • High Acetyl CoA: Fast cycle; low Acetyl CoA: Slow cycle.
  • **Examples: **
    • Citrate in high ATP conditions shuttles acetyl CoA out for fatty acid synthesis, slowing CAC.
    • Amino acids convert into CAC intermediates during starvation.

Key Irreversible Reactions in CAC

  • Characteristics: Large negative ΔG, good targets for regulation.
  • Key Reactions:
    1. Oxaloacetate + Acetyl CoA → Citrate (Citrate Synthase)
    2. Isocitrate → α-ketoglutarate (Isocitrate Dehydrogenase)
    3. α-ketoglutarate → Succinyl CoA (α-Ketoglutarate Dehydrogenase)

Allosteric Regulators

Inhibitors

  • NADH: Product of CAC; signals to slow down CAC as it accumulates.
    • Inhibits: Citrate Synthase, Isocitrate Dehydrogenase, α-Ketoglutarate Dehydrogenase.
  • ATP: High ATP signals sufficient energy, slows CAC.
    • Inhibits: Citrate Synthase, Isocitrate Dehydrogenase.
  • Products: Feedback inhibition.
    • Citrate: Inhibits Citrate Synthase.
    • Succinyl CoA: Inhibits Citrate Synthase, α-Ketoglutarate Dehydrogenase.

Activators

  • ADP: Signals low ATP, activates CAC to produce more ATP.
    • Activates: Citrate Synthase, Isocitrate Dehydrogenase.
  • Calcium (Ca2+): Influx during muscle contraction signals high energy need.
    • Activates: Isocitrate Dehydrogenase, α-Ketoglutarate Dehydrogenase.