USMLE

Regulation by Fructose-2,6-Bisphosphate (F-2,6-BP)

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Biochemical Pathways
  1. Glycolysis
  2. Citric Acid Cycle (TCA Cycle)
  3. Electron Transport Chain (ETC)
  4. Cori Cycle
  5. De Novo Purine Synthesis
  6. De Novo Pyrimidine Synthesis
  7. Purine Salvage
  8. Purine Excretion
  9. Ethanol Metabolism
  10. Pyruvate Metabolism
  11. HMP Shunt (Pentose Phosphate Pathway)
  12. Galactose Metabolism
  13. Sorbitol (Polyol) Pathway
  14. Urea Cycle
  15. Alanine (Cahill) Cycle
  16. Catecholamine Synthesis & Breakdown
  17. Homocysteine Metabolism
  18. Fatty Acid Synthesis (Citrate Shuttle)
  19. Fatty Acid Breakdown (Carnitine Shuttle)
  20. Propionic Acid Pathway
  21. Fructose Metabolism
  22. Regulation by Fructose-2,6-Bisphosphate (F-2,6-BP)
  23. Glycogenesis

Summary

Fructose-2,6-bisphosphate is a form of fructose with 2 phosphate groups attached to positions 2 and 6, that plays key roles in regulating whether cells primarily engage in glucose-consuming or glucose-forming activities.

In the fasting state with low glucose available in blood, the actions of glucagon and epinephrine dominate. These hormones activate signaling pathways in the cell that increase the levels of FBPase2, and decrease the levels of PFK2. This results in an overall decrease in fructose-2,6-bisphosphate levels, which in turn reduces PFK1 activity. The end result is less glycolysis and more gluconeogenesis in the cell.

On the other hand, in the fed state with high glucose in the blood, the actions of insulin dominate. Insulin works through a signaling pathway to decrease the level of FBPase2, and increase the levels of PFK2. This causes an overall increase in fructose-2,6-bisphosphate, which leads to an increase in PFK1 activity. The end result is more glycolysis and less gluconeogenesis in the cell.

Key Points

  • Regulation by Fructose-2,6-bisphosphate (F-2,6-BP)
    • Overview
      • Fructose-2,6-bisphosphate is a potent stimulator of PFK-1, the rate-limiting step of glycolysis
      • Levels of fructose-2,6-bisphosphate depend on relative amounts of:
        • Synthesis by phosphofructokinase-2 (PFK-2)
        • Breakdown by fructose bisphosphatase (FBPase-2)
      • PFK-2 and FBPase-2 are the same bifunctional enzyme
        • Which version dominates is determined by phosphorylation via protein kinase A (PKA)
        • PKA signaling is determined by hormonal signaling
    • Fasting state
      • Increased glucagon and epinephrine activity → increased cAMP → increased PKA
        • Increased FBPase-2
        • Decreased PFK-2
      • Less fructose-2,6-bisphosphate produced
        • Less stimulation of PFK-1 leads to less glycolysis
          • More gluconeogenesis is favored; net effect is synthesis of new glucose by liver
    • Fed state
      • Increased insulin activity → decreased cAMP → decreased PKA
        • Decreased FBPase-2
        • Increased PFK-2
      • More fructose-2,6-bisphosphate produced
        • Stimulates PFK-1 to promote more glycolysis
          • Less gluconeogenesis occurs in the liver; net effect is breakdown of glucose from blood