Fructose-2,6-bisphosphate (F-2,6-BP) is the most potent allosteric activator of phosphofructokinase-1 (PFK-1). The enzyme that synthesizes F-2,6-BP is bifunctional (PFK-2/FBPase-2). When glucagon acts on the liver, what happens to F-2,6-BP levels and the resultant metabolic effect?

• A F-2,6-BP rises; glycolysis is stimulated and gluconeogenesis is inhibited
• B F-2,6-BP rises; fructose-1,6-bisphosphatase is activated, promoting gluconeogenesis
• C F-2,6-BP falls; PFK-1 activity decreases, slowing glycolysis and favoring gluconeogenesis ✓
• D F-2,6-BP falls; PFK-2 is dephosphorylated, increasing its kinase activity

Explanation

Glucagon raises cAMP and activates PKA, which phosphorylates the bifunctional PFK-2/FBPase-2 enzyme. Phosphorylation activates the FBPase-2 domain (degrading F-2,6-BP) and inactivates the PFK-2 domain (reducing F-2,6-BP synthesis). The resulting fall in F-2,6-BP removes the allosteric activation of PFK-1, slowing glycolysis. Simultaneously, fructose-1,6-bisphosphatase is de-repressed (F-2,6-BP is its inhibitor), promoting gluconeogenesis. This coordinated switch is critical for hepatic glucose output during fasting.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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