View source for Fructose 1,6-bisphosphatase

{{infobox protein
| Name = fructose-1,6-bisphosphatase 1
|caption= Fructose-1,6-bisphosphatase and its fructose 2,6-bisphosphate complex. Rendered from PDB [http://www.rcsb.org/pdb/explore/explore.do?structureId=3FBP 3FBP].
|image = Fructose-1.6-bisphosphatase-pdb-3FBP.png
| width = 200
| HGNCid = 3606
| Symbol = FBP1
| AltSymbols = FBP
| EntrezGene = 2203
| OMIM = 229700
| RefSeq = NM_000507
| UniProt = P09467
| PDB = 
| ECnumber = 3.1.3.11
| Chromosome = 9
| Arm = q
| Band = 22.3
| LocusSupplementaryData = 
}}
{{Infobox protein family
| Symbol = FBPase
| Name = Fructose-1-6-bisphosphatase
| image = PDB 1bk4 EBI.jpg
| width = 
| caption = crystal structure of rabbit liver fructose-1,6-bisphosphatase at 2.3 angstrom resolution
| Pfam = PF00316
| Pfam_clan = CL0171 
| InterPro = IPR000146
| SMART = 
| PROSITE = PDOC00114
| MEROPS = 
| SCOP = 1frp
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = FBPase_2
| Name = Firmicute fructose-1,6-bisphosphatase
| image = 
| width = 
| caption = 
| Pfam = PF06874
| Pfam_clan = CL0163 
| InterPro = IPR009164
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = FBPase_3
| Name = Fructose-1,6-bisphosphatase
| image = PDB 1umg EBI.jpg
| width = 
| caption = crystal structure of fructose-1,6-bisphosphatase
| Pfam = PF01950
| Pfam_clan =  
| InterPro = IPR002803
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1umg
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
'''Fructose bisphosphatase''' ({{EC number|3.1.3.11}}) is an [[enzyme]] that converts [[fructose-1,6-bisphosphate]] to [[fructose 6-phosphate]] in  [[gluconeogenesis]] and the [[Calvin cycle]] which are both [[Anabolism|anabolic pathways]]. Fructose bisphosphatase [[Catalyst|catalyses]] the reverse of the reaction which is catalysed by [[phosphofructokinase]] in [[glycolysis]].<ref name="pmid2159755">{{cite journal | vauthors = Marcus F, Harrsch PB | title = Amino acid sequence of spinach chloroplast fructose-1,6-bisphosphatase | journal = Archives of Biochemistry and Biophysics | volume = 279 | issue = 1 | pages = 151–7 | date = May 1990 | pmid = 2159755 | doi = 10.1016/0003-9861(90)90475-E }}</ref><ref name="pmid3008716">{{cite journal | vauthors = Marcus F, Gontero B, Harrsch PB, Rittenhouse J | title = Amino acid sequence homology among fructose-1,6-bisphosphatases | journal = Biochemical and Biophysical Research Communications | volume = 135 | issue = 2 | pages = 374–81 | date = Mar 1986 | pmid = 3008716 | doi = 10.1016/0006-291X(86)90005-7 }}</ref> These enzymes only catalyse the reaction in one direction each, and are regulated by metabolites such as [[fructose 2,6-bisphosphate]] so that high activity of one of the two enzymes is accompanied by low activity of the other. More specifically, fructose 2,6-bisphosphate allosterically inhibits fructose 1,6-bisphosphatase, but activates phosphofructokinase-I. Fructose 1,6-bisphosphatase is involved in many different [[metabolism|metabolic pathways]] and found in most [[organism]]s. FBPase requires metal [[ion]]s for catalysis ([[Magnesium|Mg]]<sup>2+</sup> and [[Manganese|Mn]]<sup>2+</sup> being preferred) and the enzyme is potently inhibited by [[Lithium|Li]]<sup>+</sup>.

== Structure ==

The [[protein folding|fold]] of fructose-1,6-bisphosphatase from [[pig]] was noted to be identical to that of inositol-1-phosphatase (IMPase).<ref name="pmid8382485">{{cite journal | vauthors = Zhang Y, Liang JY, Lipscomb WN | title = Structural similarities between fructose-1,6-bisphosphatase and inositol monophosphatase | journal = Biochemical and Biophysical Research Communications | volume = 190 | issue = 3 | pages = 1080–3 | date = Feb 1993 | pmid = 8382485 | doi = 10.1006/bbrc.1993.1159 }}</ref> [[Inositol]] polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a [[sequence motif]] ([[Aspartic acid|Asp]]-[[Proline|Pro]]-[[Isoleucine|Ile]]/[[Leucine|Leu]]-Asp-[[Glycine|Gly]]/[[Serine|Ser]]-[[Threonine|Thr]]/Ser) which has been shown to [[Molecular binding|bind]] metal [[ions]] and participate in catalysis. This [[protein motif|motif]] is also found in the distantly-related [[fungal]], [[bacteria]]l and [[Saccharomyces cerevisiae|yeast]] IMPase [[Homology (biology)|homologues]]. It has been suggested that these [[protein]]s define an ancient [[structurally]] conserved family involved in diverse [[metabolism|metabolic]] pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly [[quinone]] [[metabolism]].<ref name="pmid7761465">{{cite journal | vauthors = York JD, Ponder JW, Majerus PW | title = Definition of a metal-dependent/Li(+)-inhibited phosphomonoesterase protein family based upon a conserved three-dimensional core structure | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 11 | pages = 5149–53 | date = May 1995 | pmid = 7761465 | pmc = 41866 | doi = 10.1073/pnas.92.11.5149 }}</ref>

== Species distribution ==

Three different groups of FBPases have been identified in [[eukaryotes]] and [[bacteria]] (FBPase I-III).<ref name="pmid10986273">{{cite journal | vauthors = Donahue JL, Bownas JL, Niehaus WG, Larson TJ | title = Purification and characterization of glpX-encoded fructose 1, 6-bisphosphatase, a new enzyme of the glycerol 3-phosphate regulon of Escherichia coli | journal = Journal of Bacteriology | volume = 182 | issue = 19 | pages = 5624–7 | date = Oct 2000 | pmid = 10986273 | pmc = 111013 | doi = 10.1128/jb.182.19.5624-5627.2000 }}</ref> None of these groups have been found in [[archaea]] so far, though a new group of FBPases (FBPase IV) which also show [[inositol monophosphatase]] activity has recently been identified in archaea.<ref name="pmid11062561">{{cite journal | vauthors = Stec B, Yang H, Johnson KA, Chen L, Roberts MF | title = MJ0109 is an enzyme that is both an inositol monophosphatase and the 'missing' archaeal fructose-1,6-bisphosphatase | journal = Nature Structural Biology | volume = 7 | issue = 11 | pages = 1046–50 | date = Nov 2000 | pmid = 11062561 | doi = 10.1038/80968 }}</ref>

A new group of FBPases (FBPase V) is found in [[thermophilic]] archaea and the hyperthermophilic [[bacterium]] ''[[Aquifex aeolicus]]''.<ref name="pmid12065581">{{cite journal | vauthors = Rashid N, Imanaka H, Kanai T, Fukui T, Atomi H, Imanaka T | title = A novel candidate for the true fructose-1,6-bisphosphatase in archaea | journal = The Journal of Biological Chemistry | volume = 277 | issue = 34 | pages = 30649–55 | date = Aug 2002 | pmid = 12065581 | doi = 10.1074/jbc.M202868200 }}</ref> The characterised members of this group show strict [[substrate specificity]] for FBP and are suggested to be the true FBPase in these [[organism]]s.<ref name="pmid12065581"/><ref name="pmid15274916">{{cite journal | vauthors = Nishimasu H, Fushinobu S, Shoun H, Wakagi T | title = The first crystal structure of the novel class of fructose-1,6-bisphosphatase present in thermophilic archaea | journal = Structure | volume = 12 | issue = 6 | pages = 949–59 | date = Jun 2004 | pmid = 15274916 | doi = 10.1016/j.str.2004.03.026 }}</ref> A [[secondary structure|structural]] study suggests that FBPase V has a novel [[protein folding|fold]] for a [[sugar]] [[phosphatase]], forming a four-layer alpha-beta-beta-alpha sandwich, unlike the more usual five-layered alpha-beta-alpha-beta-alpha arrangement.<ref name="pmid15274916"/> The arrangement of the [[catalytic]] [[side chain]]s and metal [[ligands]] was found to be consistent with the three-metal [[ion]] assisted catalysis mechanism proposed for other FBPases.

The fructose 1,6-bisphosphatases found within the [[Firmicutes]] (low GC [[Gram-positive]] bacteria) do not show any significant [[sequence (biology)|sequence]] similarity to the [[enzymes]] from other [[organism]]s. The ''[[Bacillus subtilis]]'' enzyme is inhibited by [[Adenosine monophosphate|AMP]], though this can be overcome by [[phosphoenolpyruvate]], and is dependent on Mn(2+).<ref name="pmid221467">{{cite journal | vauthors = Fujita Y, Freese E | title = Purification and properties of fructose-1,6-bisphosphatase of Bacillus subtilis | journal = The Journal of Biological Chemistry | volume = 254 | issue = 12 | pages = 5340–9 | date = Jun 1979 | pmid = 221467 | doi =  }}</ref><ref name="pmid9696785">{{cite journal | vauthors = Fujita Y, Yoshida K, Miwa Y, Yanai N, Nagakawa E, Kasahara Y | title = Identification and expression of the Bacillus subtilis fructose-1, 6-bisphosphatase gene (fbp) | journal = Journal of Bacteriology | volume = 180 | issue = 16 | pages = 4309–13 | date = Aug 1998 | pmid = 9696785 | pmc = 107433 | doi =  }}</ref> [[Mutant]]s lacking this enzyme are apparently still able to grow on gluconeogenic growth substrates such as [[malate]] and [[glycerol]].

<gallery>
 Image:Beta-D-fructose-1,6-bisphosphate wpmp.png |[[Fructose 1,6-bisphosphate]]
 Image:Beta-D-fructose-6-phosphate wpmp.png |[[Fructose 6-phosphate]]
</gallery>

==Interactive pathway map==
{{GlycolysisGluconeogenesis_WP534|highlight=Fructose_1,6-bisphosphatase}}

==Hibernation and cold adaptation==

Fructose 1,6-bisphosphatase also plays a key role in [[hibernation]], which requires strict regulation of [[Metabolism|metabolic]] processes to facilitate entry into hibernation, maintenance, arousal from hibernation, and adjustments to allow long-term [[dormancy]].<ref name="Storey">Storey, Kenneth B. "Metabolic regulation in mammalian hibernation: enzyme and protein adaptations." Comparative Biochemistry and Physiology 118A.4 (1997). 1115-1124. Web.</ref><ref name="Heldmaier">Heldmaier, Gerhard, Sylvia Ortmann, and Ralf Elvert. "Natural hypometabolism during hibernation and daily torpor in mammals." Respiratory Physiology & Neurobiology 141 (2004). 317-329. Web.</ref><ref name="Brooks">Brooks, Stephen P.J. and Kenneth B. Storey. "Mechanisms of glycolytic control during hibernation in the ground squirrel Spermophilus lateralis." Journal of Comparative Physiology B 162 (1992). 23-28. Web.</ref> During hibernation, an animal's metabolic rate may decrease to around 1/25 of its euthermic resting metabolic rate.<ref name="Heldmaier" /><ref name="Brooks" /><ref name="MacDonald">MacDonald, Justin A. and Kenneth B. Storey. "Purification and characterization of fructose bisphosphate aldolase from the ground squirrel, Spermophilus lateralis: enzyme role in mammalian hibernation." Archives of Biochemistry and Biophysics 408.2 (2002). 279-285. Web.</ref> Studies have found that FBPase is modified in hibernating animals to be much more temperature sensitive than it is in euthermic animals.<ref name="Storey" /><ref name="Brooks" /><ref name="MacDonald" /> In one study, FBPase in the liver of a hibernating bat showed a 75% decrease in K<sub>m</sub> for its substrate FBP at 5&nbsp;°C than at 37&nbsp;°C.<ref name="Storey" /> However, in a euthermic bat this decrease was only 25%, demonstrating the difference in temperature sensitivity between hibernating and euthermic bats.<ref name="Storey" /> When sensitivity to [[Allosteric regulation|allosteric]] inhibitors such as [[Adenosine monophosphate|AMP]], ADP, inorganic phosphate, and [[Fructose 2,6-bisphosphate|fructose-2,6-bisphosphate]] were examined, FBPase from hibernating bats was much more sensitive to inhibitors at low temperature than in euthermic bats.<ref name="Storey" /><ref name="Ekdahl">Ekdahl, Kristina Nilsson and Pia Ekman. "The effect of fructose 1,6-bisphosphate and AMP on the activity of phosphorylated and unphosphorylated fructose-1,6-bisphosphatase from rat liver." Federation of European Biological Societies Letters 167.2 (1984). 203-209. Web.</ref><ref name="Taketa">Taketa, Kazuhisa, and Burton M. Pogell. "Allosteric Inhibition of Rat Liver Fructose 1,6-Diphosphatase by Adenosine 5'-Monophosphate*." Journal of Biological Chemistry 240.2 (1965): 651-62. Print.</ref>

During hibernation, respiration also dramatically decreases, resulting in conditions of relative [[Hypoxia (medical)|anoxia]] in the tissues. Anoxic conditions inhibit [[gluconeogenesis]], and therefore FBPase, while stimulating [[glycolysis]], and this is another reason for reduced FBPase activity in hibernating animals.<ref name="Underwood">Underwood, A.H. and E.A. Newsholme. "Control of glycolysis and gluconeogenesis in rat kidney cortex slices." Biochemistry Journal 104 (1967). 300-305. Web.</ref> The substrate of FBPase, fructose 1,6-bisphosphate, has also been shown to activate [[pyruvate kinase]] in glycolysis, linking increased glycolysis to decreased gluconeogenesis when FBPase activity is decreased during hibernation.<ref name="Brooks" />

In addition to hibernation, there is evidence that FBPase activity varies significantly between warm and cold seasons even for animals that do not hibernate.<ref name="Fischer">Fischer, E.H., E.G. Krebs, H. Neurath, and E.R. Stadtman. "Metabolic interconversion of enzymes." Third International Symposium held in Seattle. 1973. Web.</ref>
In rabbits exposed to cold temperatures, FBPase activity decreased throughout the duration of cold exposure, increasing when temperatures became warmer again.<ref name="Fischer" /> The mechanism of this FBPase inhibition is thought to be digestion of FBPase by [[Lysosome|lysosomal]] [[protease]]s, which are released at higher levels during colder periods.<ref name="Fischer" /> Inhibition of FBPase through [[proteolytic]] digestion decreases gluconeogenesis relative to glycolysis during cold periods, similar to hibernation.<ref name="Fischer" />

Fructose 1,6-bisphosphate aldolase is another temperature dependent enzyme that plays an important role in the regulation of glycolysis and gluconeogenesis during hibernation.<ref name="MacDonald" /> Its main role is in glycolysis instead of gluconeogenesis, but its [[substrate (biochemistry)|substrate]] is the same as FBPase's, so its activity affects that of FBPase in gluconeogenesis. [[Aldolase]] shows similar changes in activity to FBPase at colder temperatures, such as an upward shift in optimum pH at colder temperatures. This adaptation allows enzymes such as FBPase and fructose-1,6-bisphosphate aldolase to track intracellular pH changes in hibernating animals and match their activity ranges to these shifts.<ref name="MacDonald" /> Aldolase also complements the activity of FBPase in anoxic conditions (discussed above) by increasing glycolytic output while FBPase inhibition decreases gluconeogenesis activity.<ref name="Dawson">Dawson, Neal J., Kyle K. Biggar, and Kenneth B. Storey. "Characterization of fructose-1,6-bisphosphate aldolase during anoxia in the tolerant turtle, Trachemys scripta elegans: an assessment of enzyme activity, expression, and structure." Institute of Biochemistry & Department of Biology, Carleton University, Ottawa, Ontario, Canada. 8.7 (2013). Web.</ref>

==Diabetes==

Fructose 1,6-bisphosphatase is also a key player in treating [[Diabetes mellitus type 2|type 2 diabetes]]. In this disease, [[hyperglycemia]] causes many serious problems, and treatments often focus on lowering blood sugar levels.<ref name="Dang">Dang, Qun, Paul D. Van Poelje, and Mark D. Erion. “The discovery and development of MB07803, a second-generation fructose-1,6-bisphosphatase inhibitor with improved pharmokinetic properties, as a potential treatment of type 2 diabetes.” RSC Drug Discoveries Series No 27. 2012. 306-323.Web.</ref><ref name="Hofmann">Hofmann, F.B. and Munchen. “Handbook of experimental pharmacology: Diabetes – perspectives in drug therapy.” Springer-Verlag Berlin Heidelverg 203 (2011). Web.</ref><ref name="Poelje">Poelje, P. D. Van, S. C. Potter, V. C. Chandramouli, et al. "Inhibition of Fructose 1,6-Bisphosphatase Reduces Excessive Endogenous Glucose Production and Attenuates Hyperglycemia in Zucker Diabetic Fatty Rats." Diabetes 55.6 (2006): 1747-754. Web.</ref> Gluconeogenesis in the liver is a major cause of glucose overproduction in these patients, and so inhibition of gluconeogenesis is a reasonable way to treat type 2 diabetes. FBPase is a good enzyme to target in the gluconeogenesis pathway because it is rate-limiting and controls the incorporation of all three-carbon substrates into glucose but is not involved in glycogen breakdown and is removed from mitochondrial steps in the pathway.<ref name="Dang" /><ref name="Hofmann" /><ref name="Poelje" /> This means that altering its activity can have a large effect on gluconeogenesis while reducing the risk of [[hypoglycemia]] and other potential side effects from altering other enzymes in gluconeogenesis.<ref name="Dang" /><ref name="Hofmann" /> In 1993, two East Asian plants that were known to have hypoglycemic effects were tested on rats. Both resulted in lowered levels of FBPase and therefore reduced gluconeogenesis and lowered blood sugar.<ref name="Shibib">Shibib, B. A., L. A. Khan, and R. Rahman. "Hypoglycaemic Activity of Coccinia Indica and Momordica Charantia in Diabetic Rats: Depression of the Hepatic Gluconeogenic Enzymes Glucose-6-phosphatase and Fructose-1,6-bisphosphatase and Elevation of Both Liver and Red-cell Shunt Enzyme Glucose-6-phosphate Dehydrogenase." Biochemical Journal 292.1 (1993): 267-70. Web.</ref> Two years later, a drug called [[Troglitazone]] (shown below) that also targets FBPase was successfully tested on mice and resulted in suppressed gluconeogenesis.<ref name="Fujiwara">Fujiwara, Toshihiko, Akira Okuno, Shinji Yoshioka, et al. "Suppression of Hepatic Gluconeogenesis in Long-term Troglitazone Treated Diabetic KK and Mice." Metabolism 44.4 (1995): 486-90. Web.</ref> More recently, drugs been developed that mimic the inhibitory activity of AMP (shown below) on FBPase, though the first such drug caused dangerous side effects.<ref name="Dang" /><ref name="Poelje" /> Efforts were made to mimic the allosteric inhibitory effects of AMP while making the drug as structurally different from it as possible.<ref name="Erion">Erion, M. D., P. D. Van Poelje, Q. Dang, et al. "MB06322 (CS-917): A Potent and Selective Inhibitor of Fructose 1,6-bisphosphatase for Controlling Gluconeogenesis in Type 2 Diabetes." Proceedings of the National Academy of Sciences 102.22 (2005): 7970-975. Web.</ref><ref name="Poelje" /> Second-generation FBPase inhibitors have now been developed and have had good results in clinical trials with non-human mammals and now humans.<ref name="Dang" /> These second-generation FBPase inhibitors could soon be good candidates for treating type 2 diabetes.

[[File:Adenosine monophosphate molecular diagram.jpg|thumb|left|baseline||AMP]]
[[File:Troglitazone.jpg|thumb|left|baseline||Troglitazone]]

== See also ==
*[[Fructose bisphosphatase deficiency]]
*[[Fructose]]
*[[Gluconeogenesis]]
*[[Metabolism]]

== References ==
{{reflist|33em}}

== Further reading ==
* {{cite book | first = Jeremy Mark | last = Berg |author2=John L. Tymoczko |author3=Lubert Stryer | year = 2002 | title = Biochemistry | chapter = Glycolysis and Gluconeogenesis | editor = Susan Moran (ed.) | edition = 5th | publisher = W. H. Freeman and Company | location = 41 Madison Avenue, New York, New York | isbn = 0-7167-3051-0 | url = https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=fructose+bisphosphatase+AND+stryer%5Bbook%5D+AND+216199%5Buid%5D&rid=stryer.section.2281#2284}}

== External links ==
* {{MeshName|Fructose-1,6-Biphosphatase}}

{{InterPro content|IPR000146}}

{{InterPro content|IPR009164}}

{{InterPro content|IPR002803}}

{{Glycolysis enzymes}}
{{Esterases}}
{{Enzymes}}
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[[Category:EC 3.1.3]]
[[Category:Protein families]]