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 Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...

and

gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...

. Fru-2,6-''P''₂ itself is synthesized and broken down by the bifunctional enzyme

phosphofructokinase 2 Phosphofructokinase-2 ( 6-phosphofructo-2-kinase, PFK-2) or fructose bisphosphatase-2 (FBPase-2), is an enzyme indirectly responsible for regulating the rates of glycolysis and gluconeogenesis in cells. It catalyzes formation and degradation ...

fructose-2,6-bisphosphatase Phosphofructokinase-2 ( 6-phosphofructo-2-kinase, PFK-2) or fructose bisphosphatase-2 (FBPase-2), is an enzyme indirectly responsible for regulating the rates of glycolysis and gluconeogenesis in cells. It catalyzes formation and degradation ...

(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 ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...

. 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 Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...

, and

epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...

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 A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modif ...

, 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

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 The Calvin cycle, light-independent reactions, bio synthetic phase, dark reactions, or photosynthetic carbon reduction (PCR) cycle of photosynthesis is a series of chemical reactions that convert carbon dioxide and hydrogen-carrier compounds into ...

. 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 Sucrose, a disaccharide, is a sugar composed of glucose and fructose subunits. It is produced naturally in plants and is the main constituent of white sugar. It has the molecular formula . For human consumption, sucrose is extracted and refined ...

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.

References

{{DEFAULTSORT:Fructosebisphosphate26 Monosaccharide derivatives Organophosphates

Effects on glucose metabolism

Production regulation

Regulation of sucrose production

See also

References