Fructose-2,6-bisphosphate (F-2,6-BP) is a potent allosteric regulator of hepatic carbohydrate metabolism. What is the effect of elevated F-2,6-BP on gluconeogenesis?

• A F-2,6-BP activates fructose-1,6-bisphosphatase (FBPase-1), promoting gluconeogenesis and glycogen synthesis
• B F-2,6-BP activates glucokinase, increasing glucose phosphorylation and preventing its release into the bloodstream
• C F-2,6-BP inhibits fructose-1,6-bisphosphatase (FBPase-1) and activates phosphofructokinase-1 (PFK-1), thus stimulating glycolysis and inhibiting gluconeogenesis simultaneously ✓
• D F-2,6-BP is a competitive inhibitor of phosphoglucose isomerase, blocking glycolysis at the second step

Explanation

Fructose-2,6-bisphosphate is produced by phosphofructokinase-2 (PFK-2) in the fed state (insulin-stimulated). It is the most potent allosteric activator of PFK-1 (glycolysis key enzyme) and simultaneously inhibits fructose-1,6-bisphosphatase (FBPase-1, the gluconeogenesis key enzyme at the same step). This dual action ensures that when F-2,6-BP is high (fed state), glycolysis is active and gluconeogenesis is suppressed. In fasting (glucagon elevates cAMP → PKA phosphorylates bifunctional PFK-2/FBPase-2 enzyme → shifts activity to FBPase-2), F-2,6-BP levels fall, relieving inhibition of FBPase-1 and allowing gluconeogenesis.

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

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