Fructose-1,6-bisphosphatase (FBPase-1) is the key regulated enzyme of gluconeogenesis. It is allosterically inhibited by fructose-2,6-bisphosphate (F-2,6-BP). F-2,6-BP levels are controlled by which bifunctional enzyme, and how does glucagon regulate this?

• A Phosphofructokinase-2/FBPase-2; glucagon → PKA → phosphorylates PFK-2 domain → lowers F-2,6-BP → activates FBPase-1 ✓
• B Phosphofructokinase-1; glucagon directly activates PFK-1 to produce F-2,6-BP
• C Pyruvate kinase; glucagon inhibits PK reducing F-2,6-BP production
• D Fructose bisphosphate aldolase; glucagon activates it to cleave F-1,6-BP and reduce F-2,6-BP

Explanation

Fructose-2,6-bisphosphate (F-2,6-BP) is synthesized and degraded by a bifunctional enzyme, PFK-2/FBPase-2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase). When insulin predominates, the kinase domain is active and F-2,6-BP levels are high, stimulating glycolysis (PFK-1 activation) and inhibiting gluconeogenesis (FBPase-1 inhibition). When glucagon is released (fasting), it activates PKA via cAMP, which phosphorylates the bifunctional enzyme, activating the FBPase-2 domain and inactivating the kinase domain — lowering F-2,6-BP. This relieves FBPase-1 inhibition and activates gluconeogenesis, while simultaneously removing PFK-1 activation and suppressing glycolysis. This is a reciprocal regulatory switch.

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

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