Fructose 2,6-bisphosphate
{{chembox
| Verifiedfields = changed
| verifiedrevid = 451629340
| ImageFile = Fructose 2,6-bisphosphate.svg
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| IUPACName = 2,6-Di-O-phosphono-β-D-fructofuranose
| OtherNames =
|Section1={{Chembox Identifiers
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 94762
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C6H14O12P2/c7-2-6(18-20(13,14)15)5(9)4(8)3(17-6)1-16-19(10,11)12/h3-5,7-9H,1-2H2,(H2,10,11,12)(H2,13,14,15)/t3-,4-,5+,6+/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = YXWOAJXNVLXPMU-ZXXMMSQZSA-N
| CASNo_Ref = {{cascite|correct|??}}
| CASNo = 79082-92-1
| PubChem = 105021
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 28602
| SMILES = C([C@@H]1[C@H]([C@@H]([C@](O1)(CO)OP(=O)(O)O)O)O)OP(=O)(O)O
| MeSHName = fructose+2,6-bisphosphate
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|Section2={{Chembox Properties
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| H=14
| O=12
| P=2
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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. {{cite journal |last1=Alfarouk |first1=Khalid O. |last2=Verduzco |first2=Daniel |last3=Rauch |first3=Cyril |last4=Muddathir |first4=Abdel Khalig |last5=Bashir |first5=Adil H. H. |last6=Elhassan |first6=Gamal O. |last7=Ibrahim |first7=Muntaser E. |last8=Orozco |first8=Julian David Polo |last9=Cardone |first9=Rosa Angela |last10=Reshkin |first10=Stephan J. |last11=Harguindey |first11=Salvador |title=Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question |journal=Oncoscience |date=18 December 2014 |volume=1 |issue=12 |pages=777–802 |doi=10.18632/oncoscience.109|pmid=25621294 |pmc=4303887 |doi-access=free }} Fru-2,6-P2 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.{{cite journal |vauthors=Wu C, Khan SA, Peng LJ, Lange AJ | title = Roles for fructose-2,6-bisphosphate in the control of fuel metabolism: beyond its allosteric effects on glycolytic and gluconeogenic enzymes | journal = Adv. Enzyme Regul. | volume = 46 | issue = 1| pages = 72–88 | year = 2006 | pmid = 16860376 | doi = 10.1016/j.advenzreg.2006.01.010 }} 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-P2 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-P2 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. The breakdown of Fru-2,6-P2 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 Pi.{{cite journal |vauthors=Kurland IJ, Pilkis SJ | title = Covalent control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: insights into autoregulation of a bifunctional enzyme | journal = Protein Sci. | volume = 4 | issue = 6 | pages = 1023–37 |date=June 1995 | pmid = 7549867 | pmc = 2143155 | doi = 10.1002/pro.5560040601 }}
Effects on glucose metabolism
Fru-2,6-P2 strongly activates glucose breakdown in glycolysis through allosteric modulation (activation) of phosphofructokinase 1 (PFK-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.{{cite web| url =http://www.cbs.umn.edu/labs/lange/KB.html| title =fructose-2,6-bisphosphate| author =Lange AJ| publisher =University of Minnesota| archive-url =https://web.archive.org/web/20100612204843/http://www.cbs.umn.edu/labs/lange/KB.html| archive-date =2010-06-12| url-status =dead}}
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-P2., 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. {{Cite book|title=Biochemistry|last1=Garret|first1=Reginald H.|last2=Grisham|first2=Charles M.|publisher=Brooks/Cole Cengage Learning|year=2013|isbn=978-1-133-10629-6|location=Belmont, CA|pages=730}}
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, glucagon, and epinephrine which affect the enzyme through phosphorylation/dephosphorylation reactions.
Activation of the glucagon receptor (primarily coupled to Gs) triggers production of cyclic adenosine monophosphate (cAMP), which activates protein kinase A (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-P2 in the cell. With decreasing amounts of Fru-2,6-P2, 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-P2 present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting gluconeogenesis.{{cite journal |vauthors=Smith WE, Langer S, Wu C, Baltrusch S, Okar DA | title = Molecular coordination of hepatic glucose metabolism by the 6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase:glucokinase complex | journal = Mol. Endocrinol. | volume = 21 | issue = 6 | pages = 1478–87 |date=June 2007 | pmid = 17374851 | doi = 10.1210/me.2006-0356 | doi-access = }} As of 2023, which specific phosphatases are involved in mediating insulin's downstream effect specifically on PFK-2 are currently unclear; protein phosphatase 1 is known to be involved in mediating insulin's downstream effect of dephosphorylating glycogen synthase, thereby activating it.
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 1/6 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.{{cite journal |vauthors=Nielsen TH, Rung JH, Villadsen D | title = Fructose-2,6-bisphosphate: a traffic signal in plant metabolism | journal = Trends Plant Sci. | volume = 9 | issue = 11 | pages = 556–63 |date=November 2004 | pmid = 15501181 | doi = 10.1016/j.tplants.2004.09.004 }}