Regulation of the Citric Acid Cycle Entry

Overview of Acetyl CoA in the Citric Acid Cycle

• Acetyl CoA is the molecule that enters the citric acid cycle.
• It's oxidized to carbon dioxide as it cycles through.
• Acetyl CoA: A two-carbon molecule with a coenzyme A (a thiol group).
• Produced from pyruvate, which is generated from glycolysis.

Conversion of Pyruvate to Acetyl CoA

• Pyruvate travels from the cytosol to mitochondria.
• Converted into Acetyl CoA by the enzyme pyruvate dehydrogenase.
  • Requires NAD+ as a cofactor, reduced to NADH.
  • Pyruvate (3-carbon) loses a carbon as CO2 in this oxidation, forming acetyl CoA (2-carbon).
  • Coenzyme A is a necessary substrate.

Irreversibility of Pyruvate to Acetyl CoA

• The reaction is irreversible, characterized by a large negative delta G.
• Irreversible reactions are targeted for regulation.
  • Once started, they continue down the pathway.

Sources of Acetyl CoA

• Fatty acids can also be broken down into acetyl CoA.
  • This acetyl CoA cannot revert to pyruvate, hence cannot be used for gluconeogenesis.

Regulation of Acetyl CoA Production

Purpose of Acetyl CoA

1. Entry into the citric acid cycle.
   • Oxidation to CO2, production of NADH, FADH2.
2. Synthesis of fatty acids when ATP levels are high.

Allosteric Regulation of Pyruvate Dehydrogenase

• Allosteric Activators:
  • CoA, NAD+, pyruvate
  • AMP (indicates low energy state)
  • Calcium (related to muscle activity/energy demand)
• Allosteric Inhibitors:
  • Acetyl CoA, NADH
  • ATP (indicates sufficient energy levels)
  • Fatty acids (indicate sufficient fat stores)

Understanding Regulation

• Substrates/Products Influence:
  • Accumulation of substrates activates.
  • Accumulation of products inhibits.
• Energy State Indicators:
  • High AMP activates (low energy state).
  • High ATP inhibits (high energy state).
  • Calcium signals energy demand in muscles.
  • Fatty acids indicate sufficient energy reserves.

Conclusion

• Regulation is crucial at irreversible steps to control metabolic flow effectively.
• Key is to understand substrate/product roles and energy signals to predict regulation.