Fructose 2,6-bisphosphate

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CASNo = 79082-92-1
PubChem = 105021
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MeSHName = fructose+2,6-bisphosphate
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Formula = C₆H₁₄O₁₂P₂
MolarMass = 340.116 g/mol
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Fructose 2,6-bisphosphate (or fructose 2,6-diphosphate), abbreviated Fru-2,6-"P"₂, is a metabolite which allosterically affects the activity of the enzymes phosphofructokinase 1 (PFK-1) and fructose 1,6-bisphosphatase (FBPase-1) to regulate glycolysis and gluconeogenesis. Fructose 2,6-bisphosphate. ]

Fru-2,6-"P"₂ is synthesized and broken down by the bifunctional enzyme, phosphofructokinase 2/fructose-2,6-bisphosphatase (PFK-2/FBPase-2). [Wu, C, Khan, S.A., Peng L.J., Lange A.J. 2006. Roles for fructose-2,6-bisphosphate in the control of fuel metabolism: beyond its allosteric effects on glycolytic and gluconeogenic enzymes. Adv. Enzyme Regul. 46: 72-88. ]

The synthesis of Fru-2,6-"P"₂ 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-"P"₂ is catalyzed by dephosphorylation by FBPase-2 to produce Fructose 6-phosphate and P_i. cite journal |author=Kurland IJ, Pilkis SJ |title=Covalent control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: insights into autoregulation of a bifunctional enzyme |url=http://www.proteinscience.org/cgi/reprint/4/6/1023 |journal=Protein Sci. |volume=4 |issue=6 |pages=1023–37 |year=1995 |pmid=7549867]

Reaction scheme of breakdown of fructose 2,6-bisphosphate to fructose 6-phosphate. [ [http://www.genome.jp/dbget-bin/www_bget?rn:R02730 KEGG REACTION: R02730 ] ]

Effects on glucose metabolism

Fru-2,6-"P"₂ strongly activates glucose breakdown in glycolysis through allosteric modulation of phosphofructokinase 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. Fructose 2,6-bisphosphate. ]

Fru-2,6-"P"₂ stimulates glucose breakdown further through reduction of gluconeogensis through allosteric inhibition of fructose 1,6-bisphosphatase. Increased levels of Fru-2,6-"P"₂ show dramatically reduced rates of FBPase-1 activity, with greater degrees of inhibition occurring at lower concentrations of Fru-2,6-"P"₂. This inhibition also appears synergistic with AMP, another allosteric inhibitor of FBPase-1. This coordination between Fru-2,6-"P"₂ and AMP allows similar inhibition of FBPase-1 with dramatically reduced levels of inhibitory AMP. Inhibition by Fru-2,6-"P"₂, however, appears reduced at elevated pH and temperature levels. [Schaftingen, E.V., Hers, H.G. 1981. Inhibition of fructose-1,6-bisphosphatase by fructose 2,6-bisphosphate. Proc. Natl. Acad. Sci. USA. 78: 2861-2863. ]

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 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-"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 dephosphorylates the enzyme to activate the PFK-2 and inhibit the FBPase-2 activities. With additional Fru-2,6-"P"₂ present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting gluconeogenesis. Kurland, I.J., Pilkis, S.J. 1995. Covalent control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: Insights into autoregulation of a bifunctional enzyme. Protein Sci. 4: 1023-1037. ] [Smith, W.E., Langer, S., Wu, C., Baltrusch, S., Okar, D.A. 2007. Molecular Coordination of Hepatic Glucose Metabolism by the 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase:Glucokinase Complex. Mol. Endocrinol. ]

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 1/6th 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. [Nielsen, T.H., Rung, J.H., Villadsen, D. 2004. Fructose-2,6-bisphosphate: a traffic signal in plant metabolism. Trends Plant Sci. 9: 556-63. ]

References

ee also

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