fructose 2,6-bisphosphate

Fructose 2,6-bisphosphate, abbreviated Fru-2,6-''P''₂, is a metabolite that allosterically affects the activity of the enzymes phosphofructokinase 1 (PFK-1) and fructose 1,6-bisphosphatase (FBPase-1) to regulate glycolysis and gluconeogenesis. Fru-2,6-''P''₂ itself is synthesized and broken down by the bifunctional enzyme phosphofructokinase 2/fructose-2,6-bisphosphatase (PFK-2/FBPase-2).

The synthesis of Fru-2,6-''P''₂ is performed through a bifunctional enzyme containing both PFK-2 and FBPase-2, which is dephosphorylated, allowing the PFK-2 portion to phosphorylate fructose 6-phosphate using ATP. The breakdown of Fru-2,6-''P''₂ is catalyzed by the phosphorylation of the bifunctional enzyme, which allows FBPase-2 to dephosphorylate fructose 2,6-bisphosphate to produce fructose 6-phosphate and P_i.

Effects on glucose metabolism

Fru-2,6-''P''₂ strongly activates glucose breakdown in glycolysis through allosteric modulation (activation) of phosphofructokinase 1 (PFK-1). Elevated expression of Fru-2,6-''P''₂ levels in the liver allosterically activates phosphofructokinase 1 by increasing the enzyme’s affinity for fructose 6-phosphate, while decreasing its affinity for inhibitory ATP and citrate. At physiological concentration, PFK-1 is almost completely inactive, but interaction with Fru-2,6-''P''₂ activates the enzyme to stimulate glycolysis and enhance breakdown of glucose.

Cellular stress as a result of oncogenesis or DNA damage among others, activates certain genes by the tumor suppressor p53. One such gene is for the expression of TP53-induced glycolysis and apoptosis regulator (TIGAR); an enzyme that inhibits glycolysis, monitors the cellular levels of reactive oxygen species, and protects cells from apoptosis. The structure of TIGAR is shown to be nearly identical to FBPase-2 on the bifunctional enzyme. TIGAR removes the allosteric effector, Fru-2,6-''P''_2., therefore the activator does not enhance the affinity of the enzyme (PFK1) for its substrate (fructose 6-phosphate). Furthermore, TIGAR also removes the glycolytic intermediate fructose 1,6-bisphosphate, the product of the PFK catalyzed third reaction of glycolysis and the substrate for the following aldolase fourth reaction of glycolysis.

Production regulation

The concentration of Fru-2,6-''P''₂ in cells is controlled through regulation of the synthesis and breakdown by PFK-2/FBPase-2. The primary regulators of this are the hormones insulin, glucagon, and epinephrine which affect the enzyme through phosphorylation/dephosphorylation reactions. Release of the hormone glucagon triggers production of cyclic adenosine monophosphate (cAMP), which activates a cAMP-dependent protein kinase. This kinase phosphorylates the PFK-2/FBPase-2 enzyme at an NH₂-terminal Ser residue with ATP to activate the FBPase-2 activity and inhibit the PFK-2 activity of the enzyme, thus reducing levels of Fru-2,6-''P''₂ in the cell. With decreasing amounts of Fru-2,6-''P''₂, glycolysis becomes inhibited while gluconeogenesis is activated. Insulin triggers the opposite response. As a phosphoprotein phosphatase, insulin dephosphorylates the enzyme, thus activating the PFK-2 and inhibiting the FBPase-2 activities. With additional Fru-2,6-''P''₂ present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting gluconeogenesis.

Regulation of sucrose production

Fru-2,6-''P''₂ plays an important role in the regulation of triose phosphates, the end products of the Calvin Cycle. In the Calvin Cycle, 5/6th of triose phosphates are recycled to make ribulose 1,5-bisphosphate. The remaining 1/6 of triose phosphate can be converted into sucrose or stored as starch. Fru-2,6-''P''₂ inhibits production of fructose 6-phosphate, a necessary element for sucrose synthesis. When the rate of photosynthesis in the light reactions is high, triose phosphates are constantly produced and the production of Fru-2,6-''P''₂ is inhibited, thus producing sucrose. Fru-2,6-''P''₂ production is activated when plants are in the dark and photosynthesis and triose phosphates are not produced.

See also

* Fructose 2,6-bisphosphatase
* Fructose 1,6-bisphosphate

References

{{DEFAULTSORT:Fructosebisphosphate26
Monosaccharide derivatives
Organophosphates