Biochemistry

Gluconeogenesis Control

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MECHANISMS OF REGULATION

  • Allosteric regulation
  • Hormonal regulation
  • Substrate availability

ALLOSTERIC REGULATION

Pyruvate carboxylase

  • 2Pyruvate + 2CO2 + 2ATP –> 2Oxaloacetate + 2ADP
  • Activated by Acetyl CoA (product of FA breakdown, marker of energy abundance & low blood glucose)

Phosphoenolpyruvate carboxykinase (PEPCK)

  • 2Oxaloacetate + 2GTP –> 2Phosphoenolpyruvate (PEP) + 2GDP + 2CO2

Corresponding glycolytic reaction

  • Pyruvate kinase: 2PEP + 2ADP –> 2Pyruvate + 2ATP
  • Inhibited by Acetyl CoA

Fructose 1,6-bisphosphatase-1 (FBP-1)

  • Fructose 1,6-BP + H2O –> Fructose 6-P + Pi
  • Activated by Citrate (CAC intermediate & marker of energy abundance)
  • Inhibited by AMP (marker of low energy) & fructose 2,6-BP (hormonally regulated)

Corresponding glycolytic reaction

  • PFK-1: Fructose 6-P + ATP –> Fructose 1,6-BP + ADP
  • Inhibited by Citrate
  • Activated by AMP & fructose 2,6-BP

SUBSTRATE AVAILABILITY

Glucose 6-phosphatase

  • Glucose-6-phosphate + H2O –> Glucose + Pi
  • Not allosterically regulated because Km >>> [glucose 6-phosphate]
  • Substrate level control

Corresponding glycolytic reaction

  • Glucokinase: Glucose + ATP –> Glucose 6-phosphate + ADP

HORMONAL REGULATION

  • FBP-2 & PFK-2 are hormonally regulated (PFK-2 inactive when phosphorylated)
  • High blood glucose = increased Insulin: glucagon ratio = PFK-2 active
    = increased fructose 2,6-BP = promote glycolysis and inhibits gluconeogenesis
  • Low blood glucose = decreased insulin: glucagon ratio = PFK-2 phosphorylated & inactive
    = decreased fructose 2,6-BP = slows glycolysis and removes inhibition from gluconeogenesis
  • INSULIN: promotes glycolysis
  • GLUCAGON: promotes gluconeogenesis

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