Fructose 2,6-bisphosphate

Fru-2,6-P2 strongly activates glucose breakdown in glycolysis through allosteric modulation (activation) of phosphofructokinase 1 (PFK-1). Elevated expression of Fru-2,6-P2 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-P2 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 encodes TP53-inducible 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-P2., 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-P2 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. Activation of the glucagon receptor (primarily coupled to Gs) triggers production of cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA, or cAMP-dependent protein kinase). PKA 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-P2 in the cell. With decreasing amounts of Fru-2,6-P2, glycolysis becomes inhibited while gluconeogenesis is activated. Insulin triggers the opposite response by activating protein phosphatases that dephosphorylate PFK-2, thereby inhibiting the FBPase-2 domain. With additional Fru-2,6-P2 present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting gluconeogenesis. As of 2023, which specific phosphatases are involved in mediating insulin's downstream effect specifically on PFK-2 are currently unclear; protein phosphatase 1 is known to be involved in mediating insulin's downstream effect of dephosphorylating glycogen synthase, thereby activating it. ==Regulation of sucrose production==

Fru-2,6-P2 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-P2 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-P2 is inhibited, thus producing sucrose. Fru-2,6-P2 production is activated when plants are in the dark and photosynthesis and triose phosphates are not produced. ==See also==