Fructose-2,6-bisphosphate (F2,6BP) is a key allosteric regulator of glycolysis and gluconeogenesis. In the fasted state, glucagon increases cAMP and activates PKA. PKA phosphorylates the bifunctional enzyme PFK-2/FBPase-2. What is the net metabolic consequence?
- A PKA phosphorylation activates PFK-2 activity, raising F2,6BP and stimulating glycolysis
- B PKA phosphorylation activates FBPase-2 and inhibits PFK-2, lowering F2,6BP, removing PFK-1 activation, and allowing FBP-1 to drive gluconeogenesis ✓
- C PKA phosphorylation activates both PFK-2 and FBPase-2 simultaneously, creating a futile cycle
- D PKA phosphorylation on the liver bifunctional enzyme has no effect on F2,6BP because hepatic FBPase-2 is constitutively active
Explanation
The hepatic bifunctional enzyme PFK-2/FBPase-2 (encoded by PFKFB1) is regulated dually by PKA-mediated phosphorylation at Ser32. When glucagon activates PKA in hepatocytes (fasted state), phosphorylation inhibits the PFK-2 kinase domain while activating the FBPase-2 phosphatase domain. This shifts the enzyme predominantly to FBPase-2 activity, degrading F2,6BP. Falling F2,6BP removes the allosteric activation of phosphofructokinase-1 (PFK-1, the rate-limiting glycolytic enzyme) and removes inhibition of fructose-1,6-bisphosphatase (FBP-1, gluconeogenic). The net result is suppression of glycolysis and activation of gluconeogenesis—appropriate for a fasted state. In cardiac muscle, the same phosphorylation activates PFK-2 (opposite isozyme response), illustrating tissue-specific regulation.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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