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Revision as of 06:24, 21 September 2011 editCheMoBot (talk | contribs)Bots141,565 edits Updating {{chembox}} (no changed fields - added verified revid - updated 'DrugBank_Ref', 'UNII_Ref', 'ChEMBL_Ref', 'ChEBI_Ref', 'KEGG_Ref', 'ChEBI_Ref') per Chem/Drugbox validation (report [[Wikipedia_talk:WikiProject_Chemicals|error← Previous edit		Latest revision as of 21:33, 13 July 2024 edit undoTeaktl17 (talk | contribs)Extended confirmed users18,081 editsm →Production regulation: +wl
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	{{chembox		{{chembox
			| Verifiedfields = changed
	| verifiedrevid = 422166759		| verifiedrevid = 451629340
	| ImageFile = Fructose 2,6-bisphosphate.svg		| ImageFile = Fructose 2,6-bisphosphate.svg
	| ImageSize =		| ImageCaption =
			| IUPACName = 2,6-Di-''O''-phosphono-β-<small>D</small>-fructofuranose
	| IUPACName =
	| OtherNames =		| OtherNames =
	| Section1 = {{Chembox Identifiers		|Section1={{Chembox Identifiers
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 21106440		| ChemSpiderID = 94762
	| InChI = 1/C7H16O12P2/c8-2-7(3-18-21(14,15)16)6(10)5(9)4(19-7)1-17-20(11,12)13/h4-6,8-10H,1-3H2,(H2,11,12,13)(H2,14,15,16)/t4-,5-,6+,7+/m1/s1
	| InChIKey = NSKBXJZGSYZROA-JWXFUTCRBS
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/C7H16O12P2/c8-2-7(3-18-21(14,15)16)6(10)5(9)4(19-7)1-17-20(11,12)13/h4-6,8-10H,1-3H2,(H2,11,12,13)(H2,14,15,16)/t4-,5-,6+,7+/m1/s1		| 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_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey = NSKBXJZGSYZROA-JWXFUTCRSA-N		| StdInChIKey = YXWOAJXNVLXPMU-ZXXMMSQZSA-N
			| CASNo_Ref = {{cascite|correct|??}}
	| CASNo = 79082-92-1		| CASNo = 79082-92-1
	| PubChem = 105021		| PubChem = 105021
			| ChEBI_Ref = {{ebicite|changed|EBI}}
	| SMILES = O=P(O)(O)OC1O(CO)(COP(O)(O)=O)(O)1O
			| ChEBI = 28602
⚫	| MeSHName = fructose+2,6-bisphosphate
			| SMILES = C(1(((O1)(CO)OP(=O)(O)O)O)O)OP(=O)(O)O
		⚫	| MeSHName = fructose+2,6-bisphosphate
	}}		}}
	| Section2 = {{Chembox Properties		|Section2={{Chembox Properties
			| C=6
	| Formula = C<sub>6</sub>H<sub>14</sub>O<sub>12</sub>P<sub>2</sub>
			| H=14
	| MolarMass = 340.116 g/mol
	| Appearance =		| O=12
			| P=2
			| Appearance =
	| Density =		| Density =
	| MeltingPt =		| MeltingPt =
	| BoilingPt =		| BoilingPt =
	}}		}}
	| Section3 = {{Chembox Hazards		|Section3={{Chembox Hazards
	| Solubility = http://books.google.fi/books?id=-Lhp0ppRYWoC&pg=PA100&dq=Fructose+2,6-bisphosphate&hl=fi&ei=-3Z5ToX0Jefa4QSN_MX2Dw&sa=X&oi=book_result&ct=result&resnum=4&ved=0CDsQ6AEwAw#v=onepage&q=Fructose%202%2C6-bisphosphate&f=false
	| MainHazards =		| MainHazards =
	| FlashPt =		| FlashPt =
	| Autoignition =		| AutoignitionPt =
	}}		}}
	}}		}}
	'''Fructose 2,6-bisphosphate''' abbreviated Fru-2,6-''P''<sub>2</sub>, is a metabolite that ] affects the activity of the enzymes ] (PFK-1) and ] (FBPase-1) to regulate ] and ].<ref name="umn">{{cite web | url = http://www.cbs.umn.edu/labs/lange/KB.html | title = fructose-2,6-bisphosphate | author = Lange AJ | authorlink = | coauthors = | date = | work = | publisher = University of Minnesota | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = }}</ref> Fru-2,6-''P''<sub>2</sub> is synthesized and broken down by the bifunctional enzyme ]/] (PFK-2/FBPase-2).<ref name="pmid16860376">{{cite journal | author = 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 | url = | issn = }}</ref>		'''Fructose 2,6-bisphosphate''', abbreviated '''Fru-2,6-''P''<sub>2</sub>''', is a metabolite that ] affects the activity of the enzymes ] (PFK-1) and ] (FBPase-1) to regulate ] and ]. <ref>{{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 }}</ref> Fru-2,6-''P''<sub>2</sub> itself is synthesized and broken down in either direction by the integrated bifunctional enzyme ] (PFK-2/FBPase-2), which also contains a phosphatase domain and is also known as fructose-2,6-bisphosphatase.<ref name="pmid16860376">{{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 }}</ref> 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''<sub>2</sub> 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''<sub>2</sub> is performed through the phosphorylation of ] using ATP by the PFK-2 portion of the enzyme. The breakdown of Fru-2,6-''P''<sub>2</sub> is catalyzed by dephosphorylation by FBPase-2 to produce Fructose 6-phosphate and P<sub>i</sub>.<ref name="kurland">{{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 | journal = Protein Sci. | volume = 4 | issue = 6 | pages = 1023–37 | year = 1995 | month = June | pmid = 7549867 | pmc = 2143155 | doi = 10.1002/pro.5560040601 | url = | issn = }}</ref>
		⚫	The synthesis of Fru-2,6-''P''<sub>2</sub> is performed through a bifunctional enzyme containing both PFK-2 and FBPase-2, which is dephosphorylated, allowing the PFK-2 portion to phosphorylate ] using ]. The breakdown of Fru-2,6-''P''<sub>2</sub> 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<sub>i</sub>.<ref name="kurland">{{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 }}</ref>
	Reaction scheme of breakdown of fructose 2,6-bisphosphate to fructose 6-phosphate.<ref></ref>		<!-- missing image? Reaction scheme of breakdown of fructose-2,6-bisphosphate to fructose-6-phosphate.<ref>[http://www.genome.jp/dbget-bin/www_bget?rn:R02730 KEGG REACTION: R02730</ref> -->
	==Effects on glucose metabolism==		==Effects on glucose metabolism==
	Fru-2,6-''P''<sub>2</sub> strongly activates ] breakdown in glycolysis through allosteric modulation of phosphofructokinase 1. Elevated expression of Fru-2,6-''P''<sub>2</sub> 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 ]. At physiological concentration, PFK-1 is almost completely inactive, but interaction with Fru-2,6-''P''<sub>2</sub> activates the enzyme to stimulate glycolysis and enhance breakdown of glucose.<ref name="umn"/>		Fru-2,6-''P''<sub>2</sub> strongly activates ] breakdown in glycolysis through allosteric modulation (activation) of phosphofructokinase 1 (PFK-1). Elevated expression of Fru-2,6-''P''<sub>2</sub> levels in the ] allosterically activates phosphofructokinase 1 by increasing the enzyme’s affinity for fructose 6-phosphate, while decreasing its affinity for inhibitory ATP and ]. At physiological concentration, PFK-1 is almost completely inactive, but interaction with Fru-2,6-''P''<sub>2</sub> activates the enzyme to stimulate glycolysis and enhance breakdown of glucose.<ref name="umn">{{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}}</ref>
			Cellular stress as a result of oncogenesis or DNA damage among others, activates certain genes by the tumor suppressor p53. One such gene encodes ] (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''<sub>2.</sub>, 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. <ref>{{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}}</ref>
	==Production regulation==		==Production regulation==
	The concentration of Fru-2,6-''P''<sub>2</sub> in cells is controlled through regulation of the synthesis and breakdown by PFK-2/FBPase-2. The primary regulators of this are the hormones ] and ], which affect the enzyme through phosphorlyation/dephosphorylation reactions. Release of the hormone glucagon triggers production of ] (cAMP), which activates a cAMP-dependent protein kinase. This kinase phosphorylates the PFK-2/FBPase-2 enzyme at an NH<sub>2</sub>-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''<sub>2</sub> in the cell. With decreasing amounts of Fru-2,6-''P''<sub>2</sub>, glycolysis becomes inhibited while gluconeogenesis is activated. Insulin triggers the opposite response. As a ], insulin dephosphorylates the enzyme, thus activating the PFK-2 and inhibiting the FBPase-2 activities. With additional Fru-2,6-''P''<sub>2</sub> present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting gluconeogenesis.<ref name="kurland"/><ref name="pmid17374851">{{cite journal | author = 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 | year = 2007 | month = June | pmid = 17374851 | doi = 10.1210/me.2006-0356 | url = | issn = }}</ref>		The concentration of Fru-2,6-''P''<sub>2</sub> in cells is controlled through regulation of the synthesis and breakdown by PFK-2/FBPase-2. The primary regulators of this are the hormones ], ], and ] which affect the enzyme through phosphorylation/dephosphorylation reactions.
			Activation of the ] (primarily coupled to ]) triggers production of ] (cAMP), which activates ] (PKA, or cAMP-dependent protein kinase). PKA phosphorylates the PFK-2/FBPase-2 enzyme at an ] 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''<sub>2</sub> in the cell. With decreasing amounts of Fru-2,6-''P''<sub>2</sub>, 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''<sub>2</sub> present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting ].<ref name="kurland"/><ref name="pmid17374851">{{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 = }}</ref> As of 2023, which specific phosphatases are involved in mediating insulin's downstream effect specifically on PFK-2 are currently unclear; ] is known to be involved in mediating insulin's downstream effect of dephosphorylating ], thereby activating it.
	==Regulation of sucrose production==		==Regulation of sucrose production==
	Fru-2,6-''P''<sub>2</sub> plays an important role in the regulation of triose phosphates, the end products of the ]. In the Calvin Cycle, 5/6th of triose phosphates are recycled to make ]. The remaining 1/6 of triose phosphate can be converted into ] or stored as starch. Fru-2,6-''P''<sub>2</sub> inhibits production of fructose 6-phosphate, a necessary element for sucrose synthesis. When the rate of ] in the light reactions is high, triose phosphates are constantly produced and the production of Fru-2,6-''P''<sub>2</sub> is inhibited, thus producing sucrose. Fru-2,6-''P''<sub>2</sub> production is activated when plants are in the dark and photosynthesis and triose phosphates are not produced.<ref name="pmid15501181">{{cite journal | author = 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 | year = 2004 | month = November | pmid = 15501181 | doi = 10.1016/j.tplants.2004.09.004 | url = | issn = }}</ref>		Fru-2,6-''P''<sub>2</sub> plays an important role in the regulation of triose phosphates, the end products of the ]. In the Calvin Cycle, 5/6th of triose phosphates are recycled to make ]. The remaining 1/6 of triose phosphate can be converted into ] or stored as starch. Fru-2,6-''P''<sub>2</sub> inhibits production of fructose 6-phosphate, a necessary element for sucrose synthesis. When the rate of ] in the light reactions is high, triose phosphates are constantly produced and the production of Fru-2,6-''P''<sub>2</sub> is inhibited, thus producing sucrose. Fru-2,6-''P''<sub>2</sub> production is activated when plants are in the dark and photosynthesis and triose phosphates are not produced.<ref name="pmid15501181">{{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 }}</ref>
	==See also==		==See also==
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	{{Reflist}}		{{Reflist}}
			{{DEFAULTSORT:Fructosebisphosphate26}}
	]		]
	]		]
	]
	]
	]
	]
	]
	]
	]