Fructose-2,6-Bisphosphate and Gluconeogenesis Regulation

The most potent allosteric regulator of the glycolysis and gluconeogenesis pathways is fructose-2,6-bisphosphate (F2,6BP). As shown in Figure 16.6, F2,6BP activates phosphofructokinase (also called PFK1) - the enzyme in glycolysis that converts fructose-6-phosphate to fructose-1,6-bisphosphate. F2,6BP also inhibits fructose-1,6-bisphosphatase (F1,6BPase) - the enzyme in gluconeogenesis that accomplishes the opposite reaction. In fact, F1,6BP is ten times more sensitive to F2,6BP than AMP, another reciprocal regulator. The complex regulatory system involving F2,6BP is shown in Figure 16.7.

A single polypeptide contains both of the activities necessary to synthesize and degrade F2,6BP. The synthetic activity is called phosphofructokinase-2 (PFK2). To distinguish PFK2 from phosphofructokinase (the glycolysis enzyme), the latter enzyme is sometimes called PFK1. The catalytic activity that breaks down F2,6BP is referred to as fructose-2,6-bisphosphatase (F2,6BPase). Interconversion of PFK2 and F2,6BPase is accomplished by a cAMP-stimulated phosphorylation of PFK2 (by cAMP-dependent protein kinase) to form F2,6BPase.

Thus, in the presence of cAMP (which is produced in response to glucagon or epinephrine action), destruction of F2,6BP is favored. Because PFK1 is stimulated by F2,6BP, but F1,6BPase (the corresponding gluconeogenesis enzyme) is inhibited by F2,6BP, cAMP produced by glucagon or epinephrine will turn off glycolysis and turn on gluconeogenesis. Thus, due to hormonal control of F2,6BP, glycolysis and gluconeogenesis respond rapidly to hormonal regulation.

Summary

> 1. F2,6BP activates PFK1 (glycolysis) and inhibits F1,6BPase (gluconeogenesis)

> 2. PFK2 makes F2,6BP from F6P

> 3. F2,6BPase breaks down F2,6BP to F6P

> 4. PFK2 is converted to F2,6BPase by cAMP-dependent protein kinase by phosphorylation (requires cAMP - stimulated by glucagon or epinephrine)

> 5. F2,6BPase is converted back to PFK2 in absence of cAMP

So, when epinephrine or glucagon stimulates cells -> cAMP is produced ->cAMP-dependent protein kinase is activated -> PFK2 is converted to F2,6BPase ->F2,6BP is broken down -> Fructose 1,6-bisphophatase (gluconeogenesis) is activated and PFK1 (glycolysis) is inhibited.

In the absence of epinephrine/glucagon stimulation (or with insulin stimulation), cAMP is broken down -> cAMP-dependent protein kinase is inactivated -> F2,6BPase is converted to PFK2 -> F2,6BP is made -> PFK1 (glycolysis) is stimulated and fructose-1,6-bisphsophatase (gluconeogenesis) is inhibited.

See also: Regulation of Gluconeogenesis, Reciprocal Regulation