Gluconeogenesis - Overcoming Irreversible Steps

Overview

• Gluconeogenesis: The creation of new glucose.
• Glycolysis: Breakdown of glucose to pyruvate.
  • Glycolysis and gluconeogenesis are essentially reverse processes.
• Purpose: To produce glucose during fasting by reversing glycolysis.
• Irreversible Steps: Three key irreversible steps in glycolysis must be overcome in gluconeogenesis.

Step 1: Pyruvate to Phosphoenolpyruvate

• Irreversible Step in Glycolysis: Pyruvate kinase converting PEP to pyruvate.
• Gluconeogenesis Pathway:
  • Step 1: Pyruvate to oxaloacetate (OAA)
    • Enzyme: Pyruvate carboxylase
    • Pyruvate (3C) + Carboxyl group = Oxaloacetate (4C)
  • Step 2: Oxaloacetate to phosphoenolpyruvate (PEP)
    • Enzyme: PEP carboxykinase
    • Requires energy: ATP and GTP
• Intermediates:
  • Amino acids: Can be converted to OAA
  • Lactate: Can be converted to pyruvate

Step 2: Fructose 1,6-bisphosphate to Fructose 6-phosphate

• Irreversible Step in Glycolysis: Phosphofructokinase converting F6P to F1,6BP.
• Gluconeogenesis Pathway:
  • Enzyme: Fructose 1,6-bisphosphatase (opposite function to kinase)
  • Phosphorylation is reversed (phosphatase removes phosphate)
• Key Point: Changing enzyme changes whole reaction pathway, not just enzyme kinetics.

Step 3: Glucose 6-phosphate to Glucose

• Irreversible Step in Glycolysis: Hexokinase converting glucose to G6P.
• Gluconeogenesis Pathway:
  • Enzyme: Glucose 6-phosphatase
  • Removes phosphate group to form glucose

Clinical Relevance

• Glucose 6-Phosphatase Deficiency:
  • People missing this enzyme cannot produce glucose from G6P.
  • Affects gluconeogenesis and glycogen breakdown.
  • Results: Severe hypoglycemia

Final Notes

• Big Takeaway: Gluconeogenesis and glycolysis are opposite processes, except for three irreversible steps that require unique reaction pathways.
• Enzymes and Names: Important mainly for understanding disease contexts.