Fructose 1,6-bisphosphatase
| fructose-1,6-bisphosphatase 1 | |
|---|---|
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Fructose-1,6-bisphosphatase and its fructose 2,6-bisphosphate complex. Rendered from PDB 3FBP. | |
| Identifiers | |
| Symbol | FBP1 |
| Alt. symbols | FBP |
| Entrez | 2203 |
| HUGO | 3606 |
| OMIM | 229700 |
| RefSeq | NM_000507 |
| UniProt | P09467 |
| Other data | |
| EC number | 3.1.3.11 |
| Locus | Chr. 9 q22.3 |
| Fructose-1-6-bisphosphatase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 crystal structure of rabbit liver fructose-1,6-bisphosphatase at 2.3 angstrom resolution | |||||||||
| Identifiers | |||||||||
| Symbol | FBPase | ||||||||
| Pfam | PF00316 | ||||||||
| Pfam clan | CL0171 | ||||||||
| InterPro | IPR000146 | ||||||||
| PROSITE | PDOC00114 | ||||||||
| SCOP | 1frp | ||||||||
| SUPERFAMILY | 1frp | ||||||||
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| Firmicute fructose-1,6-bisphosphatase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | FBPase_2 | ||||||||
| Pfam | PF06874 | ||||||||
| Pfam clan | CL0163 | ||||||||
| InterPro | IPR009164 | ||||||||
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| Fructose-1,6-bisphosphatase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 crystal structure of fructose-1,6-bisphosphatase | |||||||||
| Identifiers | |||||||||
| Symbol | FBPase_3 | ||||||||
| Pfam | PF01950 | ||||||||
| InterPro | IPR002803 | ||||||||
| SCOP | 1umg | ||||||||
| SUPERFAMILY | 1umg | ||||||||
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Fructose bisphosphatase (EC 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 anabolic pathways. Fructose bisphosphatase catalyses the reverse of the reaction which is catalysed by phosphofructokinase in glycolysis.[1][2] 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 metabolic pathways and found in most organisms. FBPase requires metal ions for catalysis (Mg2+ and Mn2+ being preferred) and the enzyme is potently inhibited by Li+.
Structure
The fold of fructose-1,6-bisphosphatase from pig was noted to be identical to that of inositol-1-phosphatase (IMPase).[3] Inositol polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a sequence motif (Asp-Pro-Ile/Leu-Asp-Gly/Ser-Thr/Ser) which has been shown to bind metal ions and participate in catalysis. This motif is also found in the distantly-related fungal, bacterial and yeast IMPase homologues. It has been suggested that these proteins define an ancient structurally conserved family involved in diverse metabolic pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly quinone metabolism.[4]
Species distribution
Three different groups of FBPases have been identified in eukaryotes and bacteria (FBPase I-III).[5] 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.[6]
A new group of FBPases (FBPase V) is found in thermophilic archaea and the hyperthermophilic bacterium Aquifex aeolicus.[7] The characterised members of this group show strict substrate specificity for FBP and are suggested to be the true FBPase in these organisms.[7][8] A structural study suggests that FBPase V has a novel 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.[8] The arrangement of the catalytic side chains 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 similarity to the enzymes from other organisms. The Bacillus subtilis enzyme is inhibited by AMP, though this can be overcome by phosphoenolpyruvate, and is dependent on Mn(2+).[9][10] Mutants lacking this enzyme are apparently still able to grow on gluconeogenic growth substrates such as malate and glycerol.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
Glycolysis and Gluconeogenesis edit
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".
Hibernation and Cold Adaptation
Fructose 1,6-bisphosphatase also plays a key role in hibernation, which requires strict regulation of metabolic processes to facilitate entry into hibernation, maintenance, arousal from hibernation, and adjustments to allow long-term dormancy.[11][12][13] During hibernation, an animal’s metabolic rate may decrease to around 1/25 of its euthermic resting metabolic rate.[12][13][14] Studies have found that FBPase is modified in hibernating animals to be much more temperature sensitive than it is in euthermic animals.[11][13][14] In one study, FBPase in the liver of a hibernating bat showed a 75% decrease in Km for its substrate FBP at 5°C than at 37°C.[11] However, in a euthermic bat this decrease was only 25%, demonstrating the difference in temperature sensitivity between hibernating and euthermic bats.[11] When sensitivity to allosteric inhibitors such as AMP, ADP, inorganic phosphate, and fructose-2,6-bisphosphate were examined, FBPase from hibernating bats was much more sensitive to inhibitors at low temperature than in euthermic bats.[11][15][16]
During hibernation, respiration also dramatically decreases, resulting in conditions of relative 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.[17] 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.[13]
In addition to hibernation, there is evidence that FBPase activity varies significantly between warm and cold seasons even for animals that do not hibernate.[18] In rabbits exposed to cold temperatures, FBPase activity decreased throughout the duration of cold exposure, increasing when temperatures became warmer again.[18] The mechanism of this FBPase inhibition is thought to be digestion of FBPase by lysosomal proteases, which are released at higher levels during colder periods.[18] Inhibition of FBPase through proteolytic digestion decreases gluconeogenesis relative to glycolysis during cold periods, similar to hibernation.[18]
Fructose 1,6-bisphosphate aldolase is another temperature dependent enzyme that plays an important role in the regulation of glycolysis and gluconeogenesis during hibernation.[14] Its main role is in glycolysis instead of gluconeogenesis, but its 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.[14] Aldolase also complements the activity of FBPase in anoxic conditions (discussed above) by increasing glycolytic output while FBPase inhibition decreases gluconeogenesis activity.[19]
Diabetes
Fructose 1,6-bisphosphatase is also a key player in treating type 2 diabetes. In this disease, hyperglycemia causes many serious problems, and treatments often focus on lowering blood sugar levels.[20][21][22] 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.[20][21][22] 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.[20][21] 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.[23] Two years later, a drug called Troglitazone (shown below) that also targets FBPase was successfully tested on mice and resulted in suppressed gluconeogenesis.[24] 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.[20][22] Efforts were made to mimic the allosteric inhibitory effects of AMP while making the drug as structurally different from it as possible.[25][22] Second-generation FBPase inhibitors have now been developed and have had good results in clinical trials with non-human mammals and now humans.[20] These second-generation FBPase inhibitors could soon be good candidates for treating type 2 diabetes.
See also
References
- ↑ Marcus F, Harrsch PB (May 1990). "Amino acid sequence of spinach chloroplast fructose-1,6-bisphosphatase". Archives of Biochemistry and Biophysics. 279 (1): 151–7. doi:10.1016/0003-9861(90)90475-E. PMID 2159755.
- ↑ Marcus F, Gontero B, Harrsch PB, Rittenhouse J (Mar 1986). "Amino acid sequence homology among fructose-1,6-bisphosphatases". Biochemical and Biophysical Research Communications. 135 (2): 374–81. doi:10.1016/0006-291X(86)90005-7. PMID 3008716.
- ↑ Zhang Y, Liang JY, Lipscomb WN (Feb 1993). "Structural similarities between fructose-1,6-bisphosphatase and inositol monophosphatase". Biochemical and Biophysical Research Communications. 190 (3): 1080–3. doi:10.1006/bbrc.1993.1159. PMID 8382485.
- ↑ York JD, Ponder JW, Majerus PW (May 1995). "Definition of a metal-dependent/Li(+)-inhibited phosphomonoesterase protein family based upon a conserved three-dimensional core structure". Proceedings of the National Academy of Sciences of the United States of America. 92 (11): 5149–53. doi:10.1073/pnas.92.11.5149. PMC 41866
. PMID 7761465. - ↑ Donahue JL, Bownas JL, Niehaus WG, Larson TJ (Oct 2000). "Purification and characterization of glpX-encoded fructose 1, 6-bisphosphatase, a new enzyme of the glycerol 3-phosphate regulon of Escherichia coli". Journal of Bacteriology. 182 (19): 5624–7. doi:10.1128/jb.182.19.5624-5627.2000. PMC 111013. PMID 10986273.
- ↑ Stec B, Yang H, Johnson KA, Chen L, Roberts MF (Nov 2000). "MJ0109 is an enzyme that is both an inositol monophosphatase and the 'missing' archaeal fructose-1,6-bisphosphatase". Nature Structural Biology. 7 (11): 1046–50. doi:10.1038/80968. PMID 11062561.
- 1 2 Rashid N, Imanaka H, Kanai T, Fukui T, Atomi H, Imanaka T (Aug 2002). "A novel candidate for the true fructose-1,6-bisphosphatase in archaea". The Journal of Biological Chemistry. 277 (34): 30649–55. doi:10.1074/jbc.M202868200. PMID 12065581.
- 1 2 Nishimasu H, Fushinobu S, Shoun H, Wakagi T (Jun 2004). "The first crystal structure of the novel class of fructose-1,6-bisphosphatase present in thermophilic archaea". Structure. 12 (6): 949–59. doi:10.1016/j.str.2004.03.026. PMID 15274916.
- ↑ Fujita Y, Freese E (Jun 1979). "Purification and properties of fructose-1,6-bisphosphatase of Bacillus subtilis". The Journal of Biological Chemistry. 254 (12): 5340–9. PMID 221467.
- ↑ Fujita Y, Yoshida K, Miwa Y, Yanai N, Nagakawa E, Kasahara Y (Aug 1998). "Identification and expression of the Bacillus subtilis fructose-1, 6-bisphosphatase gene (fbp)". Journal of Bacteriology. 180 (16): 4309–13. PMC 107433. PMID 9696785.
- 1 2 3 4 5 Storey, Kenneth B. “Metabolic regulation in mammalian hibernation: enzyme and protein adaptations.” Comparative Biochemistry and Physiology 118A.4 (1997). 1115-1124. Web.
- 1 2 Heldmaier, Gerhard, Sylvia Ortmann, and Ralf Elvert. “Natural hypometabolism during hibernation and daily torpor in mammals.” Respiratory Physiology & Neurobiology 141 (2004). 317-329. Web.
- 1 2 3 4 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.
- 1 2 3 4 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.
- ↑ 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.
- ↑ 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.
- ↑ Underwood, A.H. and E.A. Newsholme. “Control of glycolysis and gluconeogenesis in rat kidney cortex slices.” Biochemistry Journal 104 (1967). 300-305. Web.
- 1 2 3 4 Fischer, E.H., E.G. Krebs, H. Neurath, and E.R. Stadtman. “Metabolic interconversion of enzymes.” Third International Symposium held in Seattle. 1973. Web.
- ↑ 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, Ottowa, Ontario, Canada. 8.7 (2013). Web.
- 1 2 3 4 5 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.
- 1 2 3 Hofmann, F.B. and Munchen. “Handbook of experimental pharmacology: Diabetes – perspectives in drug therapy.” Springer-Verlag Berlin Heidelverg 203 (2011). Web.
- 1 2 3 4 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.
- ↑ 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." Biochem. J. Biochemical Journal 292.1 (1993): 267-70. Web.
- ↑ 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.
- ↑ 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.
Further reading
- Berg, Jeremy Mark; John L. Tymoczko; Lubert Stryer (2002). "Glycolysis and Gluconeogenesis". In Susan Moran (ed.). Biochemistry (5th ed.). 41 Madison Avenue, New York, New York: W. H. Freeman and Company. ISBN 0-7167-3051-0.
External links
- Fructose-1,6-Biphosphatase at the US National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the public domain Pfam and InterPro IPR000146
This article incorporates text from the public domain Pfam and InterPro IPR009164
This article incorporates text from the public domain Pfam and InterPro IPR002803