fructose-2,6-bisphosphate

The discovery of fructose-2,6-bisphosphate (F-2,6-P₂), the most potent regulator of carbohydrate metabolism, solved the riddle of how the hormone glucagon, via its second messenger cAMP, is able to stimulate gluconeogenesis and inhibit glycolysis in mammalian liver. High levels of F-2,6-P₂ were shown to activate 6-phosphofructo-1-kinase (PF-1-K) and inhibit fructose-1,6-bisphosphatase (FDPase), key enzymes of the fructose-6-phosphate/fructose-1,6-bisphosphate (F-6-P/F-1,6-P₂) cycle (1). These effects lead to stimulation of glycolysis and inhibition of gluconeogenesis. Fructose-2,6-bisphosphate is both synthesized and degraded by the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6-PF-2-K/F-2,6-P₂ase). The enzyme has a cAMP-dependent protein kinase site at Serine-32. Phosphorylation of the enzyme at this site decreases the synthetic kinase activity and increases the degradative bisphosphatase activity, thereby lowering F-2,6-P₂ levels. The dephosphorylation of 6-PF-2-K/F-2,6-P₂ase and subsequent rise in F-2,6-P₂ concentration is promoted by increased insulin levels, via the action of protein phosphatases. The effect of glucagon on gluconeogenesis/ glycolysis flux is mediated first by cAMP and subsequently by F-2,6-P₂. Therefore, the intracellular concentration of F-2,6-P₂ provides the final link in the chain of molecular events from the release of glucagon to the stimulation of gluconeogenesis and inhibition of glycolysis.

Link to the Protein Information Resource entry for this enzyme family.