Fructose 2,6-bisphosphate
Encyclopedia
Fructose 2,6-bisphosphate abbreviated Fru-2,6-P2, 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-P2 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-P2 is performed through the phosphorylation of fructose 6-phosphate
using ATP by the PFK-2 portion of the enzyme. The breakdown of Fru-2,6-P2 is catalyzed by dephosphorylation by FBPase-2 to produce Fructose 6-phosphate and Pi.
Reaction scheme of breakdown of fructose 2,6-bisphosphate to fructose 6-phosphate.
breakdown in glycolysis through allosteric modulation of phosphofructokinase 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.
and glucagon
, which affect the enzyme through phosphorlyation/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-P2 in the cell. With decreasing amounts of Fru-2,6-P2, 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-P2 present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting gluconeogenesis.
. 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.
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
and gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
. Fru-2,6-P2 is synthesized and broken down by the bifunctional enzyme phosphofructokinase 2
Phosphofructokinase 2
Phosphofructokinase 2 or fructose biphosphatase 2 , is an enzyme responsible for regulating the rates of glycolysis and gluconeogenesis in the human body. It is a homodimer of 55 kDa subunits arranged in a head-to-head fashion, with each polypeptide chain consisting of independent kinase and...
/fructose-2,6-bisphosphatase (PFK-2/FBPase-2).
The synthesis of Fru-2,6-P2 is performed through the phosphorylation of fructose 6-phosphate
Fructose 6-phosphate
Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...
using ATP by the PFK-2 portion of the enzyme. The breakdown of Fru-2,6-P2 is catalyzed by dephosphorylation by FBPase-2 to produce Fructose 6-phosphate and Pi.
Reaction scheme of breakdown of fructose 2,6-bisphosphate to fructose 6-phosphate.
Effects on glucose metabolism
Fru-2,6-P2 strongly activates glucoseGlucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
breakdown in glycolysis through allosteric modulation of phosphofructokinase 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
Citrate
A citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...
. 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.
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 insulinInsulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
and glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
, which affect the enzyme through phosphorlyation/dephosphorylation reactions. Release of the hormone glucagon triggers production of cyclic adenosine monophosphate
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
(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-P2 in the cell. With decreasing amounts of Fru-2,6-P2, glycolysis becomes inhibited while gluconeogenesis is activated. Insulin triggers the opposite response. As a phosphoprotein phosphatase
Phosphoprotein phosphatase
Phosphoprotein phosphatase is an enzyme that dephosphorylates certain phosphorylated proteins.In some contexts, "Phosphoprotein phosphatase" is equated with serine/threonine specific protein phosphatase, and classified under ....
, insulin dephosphorylates the enzyme, thus activating the PFK-2 and inhibiting the FBPase-2 activities. With additional Fru-2,6-P2 present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting gluconeogenesis.
Regulation of sucrose production
Fru-2,6-P2 plays an important role in the regulation of triose phosphates, the end products of the Calvin CycleCalvin cycle
The Calvin cycle or Calvin–Benson-Bassham cycle or reductive pentose phosphate cycle or C3 cycle or CBB cycle is a series of biochemical redox reactions that take place in the stroma of chloroplasts in photosynthetic organisms...
. 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
Sucrose is the organic compound commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in human nutrition. The molecule is a disaccharide composed of glucose and fructose with the molecular formula...
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
Photosynthesis
Photosynthesis is a chemical process that converts carbon dioxide into organic compounds, especially sugars, using the energy from sunlight. Photosynthesis occurs in plants, algae, and many species of bacteria, but not in archaea. Photosynthetic organisms are called photoautotrophs, since they can...
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.