Fructose 2,6-bisphosphate

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Fructose 2,6-bisphosphate
Identifiers
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MeSH fructose+2,6-bisphosphate
Properties
C6H14O12P2
Molar mass 340.116 g/mol
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)

Infobox disclaimer and references

Fructose 2,6-bisphosphate (or fructose 2,6-diphosphate), abbreviated Fru-2,6-P2, 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. [1]

Fru-2,6-P2 is synthesized and broken down by the bifunctional enzyme, phosphofructokinase 2/fructose-2,6-bisphosphatase (PFK-2/FBPase-2). [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. [3]

Reaction scheme of breakdown of fructose 2,6-bisphosphate to fructose 6-phosphate. [4]

Effects on glucose metabolism

Fru-2,6-P2 strongly activates glucose 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. [1]

Fru-2,6-P2 stimulates glucose breakdown further through reduction of gluconeogensis through allosteric inhibition of fructose 1,6-bisphosphatase. Increased levels of Fru-2,6-P2 show dramatically reduced rates of FBPase-1 activity, with greater degrees of inhibition occurring at lower concentrations of Fru-2,6-P2. This inhibition also appears synergistic with AMP, another allosteric inhibitor of FBPase-1. This coordination between Fru-2,6-P2 and AMP allows similar inhibition of FBPase-1 with dramatically reduced levels of inhibitory AMP. Inhibition by Fru-2,6-P2, however, appears reduced at elevated pH and temperature levels. [5]

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 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 dephosphorylates the enzyme to activate the PFK-2 and inhibit the FBPase-2 activities. With additional Fru-2,6-P2 present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting gluconeogenesis. [3] [6]

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 1/6th 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. [7]

References

  1. 1.0 1.1 Fructose 2,6-bisphosphate. <http://www.cbs.umn.edu/biochemistry/LangeLab/KB.html>
  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. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=16860376>
  3. 3.0 3.1 Kurland IJ, Pilkis SJ (1995). "Covalent control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: insights into autoregulation of a bifunctional enzyme". Protein Sci. 4 (6): 1023–37. PMID 7549867.
  4. http://www.genome.jp/dbget-bin/www_bget?rn:R02730
  5. 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. <http://www.pnas.org/cgi/content/abstract/78/5/2861>
  6. 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. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17374851&query_hl=1&itool=pubmed_docsum>
  7. 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. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15501181&query_hl=1&itool=pubmed_docsum>

See also



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