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 pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...

and

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

. Fru-2,6-''P''₂ itself is synthesized and broken down in either direction by the integrated bifunctional enzyme phosphofructokinase 2 (PFK-2/FBPase-2), which also contains a phosphatase domain and is also known as fructose-2,6-bisphosphatase. Whether the kinase and phosphatase domains of PFK-2/FBPase-2 are active or inactive depends on the phosphorylation state of the enzyme. Fructose-6-p-phosphate is phosphorylated by the kinase domain of PFK-2/FBPase-2 to Fru-2,6-''P''₂ when PFK-2/FBPase-2 is active in a dephosphorylated state. This dephosphorylated state is favored by high levels of insulin, which activates the phosphatase domain. 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 Fructose 6-phosphate (sometimes called the Neuberg ester) is a derivative of fructose, which has been phosphorylated at the 6-hydroxy group. It is one of several possible fructosephosphates. The β-D-form of this compound is very common in cells ...

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 Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...

breakdown in glycolysis through allosteric modulation (activation) of phosphofructokinase 1 (PFK-1). Elevated expression of Fru-2,6-''P''₂ levels in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

allosterically activates phosphofructokinase 1 by increasing the enzyme’s affinity for fructose 6-phosphate, while decreasing its affinity for inhibitory ATP and

citrate Citric acid is an organic compound with the formula . It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry Biochemistry, or biological chemistry, is the study of chemical processes within and relati ...

. 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 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-''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 insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the 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 (medic ...

, 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 a ...

which affect the enzyme through phosphorylation/dephosphorylation reactions. Activation of the glucagon receptor (primarily coupled to G_s) triggers production of

cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine tri ...

(cAMP), which activates

protein kinase A In cell biology, protein kinase A (PKA) is a family of serine-threonine kinases whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, in ...

(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-''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 by activating protein phosphatases that dephosphorylate PFK-2, thereby inhibiting the FBPase-2 domain. With additional Fru-2,6-''P''₂ present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting

. As of 2023, which specific phosphatases are involved in mediating insulin's downstream effect specifically on PFK-2 are currently unclear;

protein phosphatase 1 Protein phosphatase 1 (PP1) belongs to a certain class of phosphatases known as protein serine/threonine phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been fo ...

is known to be involved in mediating insulin's downstream effect of dephosphorylating

glycogen synthase Glycogen synthase (UDP-glucose-glycogen glucosyltransferase) is a key enzyme in glycogenesis, the conversion of glucose into glycogen. It is a glycosyltransferase () that catalyses the reaction of UDP-glucose and (1,4--D-glucosyl)n to yield UD ...

, thereby activating it.

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 Photosynthesis ( ) is a system of biological processes by which photosynthetic organisms, such as most plants, algae, and cyanobacteria, convert light energy, typically from sunlight, into the chemical energy necessary to fuel their metabo ...

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