Biology:Fructose 1,6-bisphosphatase

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Short description: Class of enzymes
fructose-1,6-bisphosphatase 1
Fructose-1.6-bisphosphatase-pdb-3FBP.png
Fructose-1,6-bisphosphatase and its fructose 2,6-bisphosphate complex. Rendered from PDB 3FBP.
Identifiers
SymbolFBP1
Alt. symbolsFBP
NCBI gene2203
HGNC3606
OMIM229700
RefSeqNM_000507
UniProtP09467
Other data
EC number3.1.3.11
LocusChr. 9 q22.3
Fructose-1-6-bisphosphatase
PDB 1bk4 EBI.jpg
crystal structure of rabbit liver fructose-1,6-bisphosphatase at 2.3 angstrom resolution
Identifiers
SymbolFBPase
PfamPF00316
Pfam clanCL0171
InterProIPR000146
PROSITEPDOC00114
SCOP21frp / SCOPe / SUPFAM
Firmicute fructose-1,6-bisphosphatase
Identifiers
SymbolFBPase_2
PfamPF06874
Pfam clanCL0163
InterProIPR009164
Fructose-1,6-bisphosphatase
1umg4.jpg
crystal structure of fructose-1,6-bisphosphatase
Identifiers
SymbolFBPase_3
PfamPF01950
InterProIPR002803
SCOP21umg / SCOPe / SUPFAM

The enzyme fructose bisphosphatase (EC 3.1.3.11; systematic name D-fructose-1,6-bisphosphate 1-phosphohydrolase) catalyses the conversion of fructose-1,6-bisphosphate to fructose 6-phosphate in gluconeogenesis and the Calvin cycle, which are both anabolic pathways:[1][2]

D-fructose 1,6-bisphosphate + H2O = D-fructose 6-phosphate + phosphate

Phosphofructokinase (EC 2.7.1.11) catalyses the reverse conversion of fructose 6-phosphate to fructose-1,6-bisphosphate, but this is not just the reverse reaction, because the co-substrates are different (and so thermodynamic requirements are not violated). The two enzymes each catalyse the conversion in one direction only, and are regulated by metabolites such as fructose 2,6-bisphosphate so that high activity of one of them 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 pigs 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 Bacillota (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

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] FBPase is modified in hibernating animals to be much more temperature sensitive than it is in euthermic animals.[11][13][14] 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

AMP

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]

Drug candidates have been developed that mimic the inhibitory activity of AMP on FBPase.[20][22] Efforts were made to mimic the allosteric inhibitory effects of AMP while making the drug as structurally different from it as possible.[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][23]

See also

References

  1. ↑ "Amino acid sequence of spinach chloroplast fructose-1,6-bisphosphatase". Archives of Biochemistry and Biophysics 279 (1): 151–7. May 1990. doi:10.1016/0003-9861(90)90475-E. PMID 2159755. 
  2. ↑ "Amino acid sequence homology among fructose-1,6-bisphosphatases". Biochemical and Biophysical Research Communications 135 (2): 374–81. Mar 1986. doi:10.1016/0006-291X(86)90005-7. PMID 3008716. 
  3. ↑ "Structural similarities between fructose-1,6-bisphosphatase and inositol monophosphatase". Biochemical and Biophysical Research Communications 190 (3): 1080–3. Feb 1993. doi:10.1006/bbrc.1993.1159. PMID 8382485. 
  4. ↑ "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. May 1995. doi:10.1073/pnas.92.11.5149. PMID 7761465. Bibcode: 1995PNAS...92.5149Y. 
  5. ↑ "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. Oct 2000. doi:10.1128/jb.182.19.5624-5627.2000. PMID 10986273. 
  6. ↑ "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. Nov 2000. doi:10.1038/80968. PMID 11062561. 
  7. ↑ 7.0 7.1 "A novel candidate for the true fructose-1,6-bisphosphatase in archaea". The Journal of Biological Chemistry 277 (34): 30649–55. Aug 2002. doi:10.1074/jbc.M202868200. PMID 12065581. 
  8. ↑ 8.0 8.1 "The first crystal structure of the novel class of fructose-1,6-bisphosphatase present in thermophilic archaea". Structure 12 (6): 949–59. Jun 2004. doi:10.1016/j.str.2004.03.026. PMID 15274916. 
  9. ↑ "Purification and properties of fructose-1,6-bisphosphatase of Bacillus subtilis". The Journal of Biological Chemistry 254 (12): 5340–9. Jun 1979. doi:10.1016/S0021-9258(18)50601-3. PMID 221467. 
  10. ↑ "Identification and expression of the Bacillus subtilis fructose-1, 6-bisphosphatase gene (fbp)". Journal of Bacteriology 180 (16): 4309–13. Aug 1998. doi:10.1128/JB.180.16.4309-4313.1998. PMID 9696785. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 "Metabolic regulation in mammalian hibernation: enzyme and protein adaptations". Comparative Biochemistry and Physiology A 118 (4): 1115–24. December 1997. doi:10.1016/S0300-9629(97)00238-7. PMID 9505421. 
  12. ↑ 12.0 12.1 "Natural hypometabolism during hibernation and daily torpor in mammals". Respiratory Physiology & Neurobiology 141 (3): 317–29. August 2004. doi:10.1016/j.resp.2004.03.014. PMID 15288602. 
  13. ↑ 13.0 13.1 13.2 13.3 Brooks, Stephen P.J.; Storey, Kenneth B. (January 1992). "Mechanisms of glycolytic control during hibernation in the ground squirrel Spermophilus lateralis". Journal of Comparative Physiology B 162 (1): 23–28. doi:10.1007/BF00257932. 
  14. ↑ 14.0 14.1 14.2 14.3 "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): 279–85. December 2002. doi:10.1016/S0003-9861(02)00579-9. PMID 12464282. 
  15. ↑ "The effect of fructose 2,6-bisphosphate and AMP on the activity of phosphorylated and unphosphorylated fructose-1,6-bisphosphatase from rat liver". FEBS Letters 167 (2): 203–9. February 1984. doi:10.1016/0014-5793(84)80127-1. PMID 6321241. 
  16. ↑ "Allosteric Inhibition of Rat Liver Fructose 1,6-Diphosphatase by Adenosine 5'-Monophosphate". The Journal of Biological Chemistry 240 (2): 651–62. February 1965. doi:10.1016/S0021-9258(17)45224-0. PMID 14275118. http://www.jbc.org/content/240/2/651.long. 
  17. ↑ "Control of glycolysis and gluconeogenesis in rat kidney cortex slices". The Biochemical Journal 104 (1): 300–5. July 1967. doi:10.1042/bj1040300. PMID 4292000. 
  18. ↑ 18.0 18.1 18.2 18.3 Metabolic Interconversion of Enzymes 1973 Third International Symposium held in Seattle, June 5-8, 1973. Berlin, Heidelberg: Springer. 1974. ISBN 978-3-642-80817-3. 
  19. ↑ "Characterization of fructose-1,6-bisphosphate aldolase during anoxia in the tolerant turtle, Trachemys scripta elegans: an assessment of enzyme activity, expression and structure". PLOS ONE 8 (7): e68830. 2013. doi:10.1371/journal.pone.0068830. PMID 23874782. Bibcode: 2013PLoSO...868830D. 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 Dang, Qun; Van Poelje, Paul D.; Erion, Mark D. (2012). "Chapter 11: The Discovery and Development of MB07803, a Second-Generation Fructose-1,6-bisphosphatase Inhibitor with Improved Pharmacokinetic Properties, as a Potential Treatment of Type 2 Diabetes". New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches. Cambridge: The Royal Society of Chemistry. doi:10.1039/9781849735322-00306. ISBN 978-1-84973-414-1. 
  21. ↑ 21.0 21.1 21.2 Arch, Jonathan R. S. (2011). "Thermogenesis and Related Metabolic Targets in Anti-Diabetic Therapy". Diabetes - Perspectives in Drug Therapy (1st ed.). Berlin, Heidelberg: Springer. p. 203. ISBN 978-3-642-17214-4. 
  22. ↑ 22.0 22.1 22.2 22.3 "Inhibition of fructose 1,6-bisphosphatase reduces excessive endogenous glucose production and attenuates hyperglycemia in Zucker diabetic fatty rats". Diabetes 55 (6): 1747–54. June 2006. doi:10.2337/db05-1443. PMID 16731838. 
  23. ↑ "Fructose-1,6-bisphosphatase inhibitors: A new valid approach for management of type 2 diabetes mellitus". European Journal of Medicinal Chemistry 141: 473–505. December 2017. doi:10.1016/j.ejmech.2017.09.029. PMID 29055870. 

Further reading

External links

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

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| title = Metabolism: carbohydrate metabolism: [[Biology:Glycoglycolysis/gluconeogenesis enzymes
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| group2 = Gluconeogenesis only
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