Phosphoglucoisomerase: Difference between revisions

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<applet load="1iat" size="300" color="white" frame="true" align="right" caption="Human phosphoglucose isomerase (1IAT)" />
<StructureSection load='1iat' size='350' side='right' scene='' caption='Human phosphoglucoisomerase complex with sulfate (PDB code [[1iat]])'>


'''Phosphoglucoisomerase''' (alternatively known as '''phosphoglucose isomerase''' or '''Glucose-6-phosphate isomerase''') are a group of enzymes of the isomerase family ([http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.1.9 EC 5.3.1.9]), so named for their main function in glycolysis and gluconeogenesis. In both these pathways phosphoglucose isomerase (PGI) is used to inter-convert glucose-6-phosphate and fructose 6-phosphate. This reaction is driven by the relative concentrations of these sugars in the cytoplasmic matrix of the cell <ref>PMID:11371164</ref>.
'''Phosphoglucoisomerase''' (alternatively known as '''phosphoglucose isomerase''' or '''Glucose-6-phosphate isomerase''') are a group of enzymes of the isomerase family ([[EC]] 5.3.1.9), so named for their main function in glycolysis and gluconeogenesis. See [[Glycolysis Enzymes]].  In both these pathways phosphoglucose isomerase (PGI) is used to inter-convert glucose-6-phosphate and fructose 6-phosphate. This reaction is driven by the relative concentrations of these sugars in the cytoplasmic matrix of the cell <ref>PMID:11371164</ref>. The overall reaction can be seen here  [[Image:Phosphoglucose_Isomerase1.pdf]].
 


Phosphoglucoisomerase is also know for a list of activities outside the cells:
Phosphoglucoisomerase is also known for a list of activities:
* Neuroleukin (NLK)- nerve growth factor. Secreted by T cells, promotes the survival of certain sensory and embryonic nerve cells. Also used to stimulate the production of immunoglobulin <ref>PMID:3764429</ref>.
* Neuroleukin (NLK)- nerve growth factor. Secreted by T cells, promotes the survival of certain sensory and embryonic nerve cells. Also used to stimulate the production of immunoglobulin <ref>PMID:3764429</ref>.
* Autocrine motility factor (AMF)- product of tumor cells, it promotes cell migration and viewed as a possible cause in cancer metastasis<ref>PMID:12054796</ref>.
* Autocrine motility factor (AMF)- product of tumor cells, it promotes cell migration and viewed as a possible cause in [[cancer]] metastasis<ref>PMID:12054796</ref>.
* Maturation factor(MF) <ref>PMID:8639816</ref>
* Maturation factor(MF) <ref>PMID:8639816</ref>
* Myofibril-bound serine protese inhibitor (MBSPI)<ref>PMID:10833440</ref>
* Myofibril-bound serine protese inhibitor (MBSPI)<ref>PMID:10833440</ref>
* PGI is important for metabolism in many different clades, including eukarya, bacteria, and archea. <ref> Hansen T, Schlichting B, Grtozinger J, Swam MK, Davies C, Schonheit P. Mutagentic and catalytically residues of cupin type phosphoglucose isomerase from Archaeoglobus fulgidus.  FEBS Journal. 2005; 272(24): 6266-75. </ref>.
* Involved in Gluconeogenesis in which it catalyzes the reaction of D-glucose to D-Fructose.


See also [[Isomerases]].
=='''Structure'''==
=='''Structure'''==
<applet load="1hox" size="400" color="white" frame="true" align="right" caption="Phosphoglucose isomerase" />
[[Image:Align.jpg|thumb|left|'''Figure 1.''' Multiple alignment PGI - ''Geobacillus stearothermophilus'' (white),'' Homo sapiens'' (pink), ''Oryctolagus cuniculus'' (blue)<ref>    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera--a visualization system for exploratory research and analysis.  J Comput Chem. 2004 Oct;25(13):1605-12. </ref>]]
[[Image:Align.jpg|thumb|left|'''Figure 1.''' Multiple alignment PGI - ''Geobacillus stearothermophilus'' (white),'' Homo sapiens'' (pink), ''Oryctolagus cuniculus'' (blue)<ref>    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera--a visualization system for exploratory research and analysis.  J Comput Chem. 2004 Oct;25(13):1605-12. </ref>]]


Phosphoglucose isomerase exists in the cell usually as a <scene name='Stancu_Phosphoglucoisomerase_Sandbox_1/Dimer/1'>homodimer</scene>, nevertheless outside of the cell, it has been isolated as a <scene name='Stancu_Phosphoglucoisomerase_Sandbox_1/Monomer/1'>monomeric</scene> structure. PGI has essentially an identical fold in all of the characterized species (see '''Figure 1'''). The <scene name='Stancu_Phosphoglucoisomerase_Sandbox_1/Sec_struct/1'>secondary structure</scene> of phosphoglucose isomerase is charaterized by an αβα conformation, on each of its two domains. The smaller domain is characterized by 5 parallel β-sheets, while the larger domain if formed out of 6 parallel/antiparallel β-sheets. Furthermore, another characteristic trait is a residue extension at the C-terminus, which wraps around the other monomer in the dimeric conformation. A "hook" that can potentially be involved in the previously mentioned extracellular activities.
Phosphoglucose isomerase exists in the cell usually as a <scene name='Stancu_Phosphoglucoisomerase_Sandbox_1/Dimer/1'>homodimer</scene>, nevertheless outside of the cell, it has been isolated as a <scene name='Stancu_Phosphoglucoisomerase_Sandbox_1/Monomer/1'>monomeric</scene> structure. PGI has essentially an identical fold in all of the characterized species (see '''Figure 1'''). The <scene name='Stancu_Phosphoglucoisomerase_Sandbox_1/Sec_struct/1'>secondary structure</scene> of phosphoglucose isomerase is charaterized by an αβα conformation, on each of its two domains. The smaller domain is characterized by 5 parallel β-sheets, while the larger domain if formed out of 6 parallel/antiparallel β-sheets. Furthermore, another characteristic trait is a residue extension at the C-terminus, which wraps around the other monomer in the dimeric conformation. A "hook" that can potentially be involved in the previously mentioned extracellular activities.


Phosphoglucose isomerase has a molecular mass of proximately 55 kDa.
Phosphoglucose isomerase has a monomer molecular mass of proximately 55 kDa.


'''Active Site''' - Mammalian PGI shows a degree of <scene name='Stancu_Phosphoglucoisomerase_Sandbox_1/Conservation2/1'>conservation</scene> ( dark red for highly conserved regions - dark blue for variable reigions) of about 90 %. The <scene name='Stancu_Phosphoglucoisomerase_Sandbox_1/Active_site/2'>active site</scene> is the region with highest observed conservation, with a number of residues that are crucial in the mechanism of the enzyme (Lys210, Gln353, Glu357, Gln511, Lys518, His388b).
'''Active Site''' - Mammalian PGI shows a degree of <scene name='Stancu_Phosphoglucoisomerase_Sandbox_1/Conservation2/1'>conservation</scene> ( dark red for highly conserved regions - dark blue for variable reigions) of about 90 %. The <scene name='Stancu_Phosphoglucoisomerase_Sandbox_1/Active_site2/1'>active site</scene> is the region with highest observed conservation, containing a number of residues that are crucial in the enzyme-substrate interaction mechanism (Lys210, Gln353, Glu357, Gln511, Lys518, His388b).  Lys518(His388) and Glu357 <scene name='Gilman_sandbox_1/Lys_518_and_glu_357/1'>Lys 518(His388) and Glu357 </scene>  are the main components of ring opening, while many of the other residues can be used for stabliziation and orientation. 
 
Another characteristic of phosphoglucose isomerase is that binding of substrate at the active site induces a small movement in the conformation of the enzyme. This can be seen in '''Figure 2''' as change in the position of an α helix.


Another characteristic of phosphoglucose isomerase is that binding of substrate at the active site, induces a small movement in the conformation of the enzyme. This can be seen in '''Figure 2''' as change in the position of an α helix.
[[Image:Active_site_movement.jpg|thumb|left|'''Figure 2.''' Substrate induced movement]]
[[Image:Active_site_movement.jpg|thumb|left|'''Figure 2.''' Substrate induced movement]]
 
</StructureSection>
__NOTOC__
=='''Mechanism'''==
=='''Mechanism'''==
The proposed reaction mechanism of PGI for the reversible conversion of glucose-6-phosphate to fructose 6-phosphate involves an acid/base catalysis by the enzyme.<ref> Voet D, Voet J, and  Pratt C. Fundamentals of Biochemistry Life at the Molecular Level. New York: John Wiley & Sons, 2008. Print.</ref>
The proposed reaction mechanism of PGI for the reversible conversion of glucose-6-phosphate to fructose 6-phosphate involves an acid/base catalysis by the enzyme (see '''Figure 3'''). The basic mechanism involves the isomerization of an aldose to a ketose.  This is performed by a ring opening, followed by an isomeration of the opened ring, then a ring closing.  A detailed step by step mechanism of this process can be seen as follows <ref> Voet D, Voet J, and  Pratt C. Fundamentals of Biochemistry Life at the Molecular Level. New York: John Wiley & Sons, 2008. Print.</ref>:


'''Step 1.''' The substrate binds to the enzyme.
'''Step 1.''' The substrate binds to the enzyme.
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'''Step 5.''' Lys518 (or His388b) abstracts back the proton from the sugar ring oxygen, resulting in a ring closure, to give the product.  
'''Step 5.''' Lys518 (or His388b) abstracts back the proton from the sugar ring oxygen, resulting in a ring closure, to give the product.  


[[Image:Mech.png]]
[[Image:Fig 15-3 2014 1420.png|700px|center|thumb| '''Figure 3.''' The reaction mechanism of phosphoglucosisomerase. The active site catalytic residues, BH<sup>+</sup> and B′, are thought to be Lys and His, respectively.<ref>''Fundamentals of Biochemistry
 
Life at the Molecular Level'' Vth Edition (2016), Donald Voet, Judith G. Voet Charlotte W. Pratt; Fig 15-3, pg 483.</ref>]]
'''Regulation'''- Phosphoglucoisomerase is regulated only by the relative concentrations of glucose-6-phosphate and fructose 6-phosphate, towards equilibrium. Nevertheless, it was found that the kinetic parameters of PGI does depend on the pH and temperature of the environment.
=='''Regulation and Inhibition'''== 
'''Regulation'''  of phosphoglucoisomerase is only done by the relative concentrations of glucose-6-phosphate and fructose 6-phosphate, towards equilibrium. Nevertheless, it was found that the kinetic parameters of PGI does depend on the pH and temperature of the environment.
The following kinetic parameters are proposed for rabbit PGI at pH 8.5 and  30°C <ref>PMID: 5647261</ref>
The following kinetic parameters are proposed for rabbit PGI at pH 8.5 and  30°C <ref>PMID: 5647261</ref>


[[Image:Kinetic_PGI.JPG]]
[[Image:Kinetic_PGI.JPG]]


It is interesting to point the regulation of PGI in other aspects that are not involved in metabolism.  For example, PGI acts as a "cytokine" outside the cell in that it can be used as a cell signalling protein.  PGI has been found to to be associated with AMF cells, which is found to regulate tumor cell motility.  Regulation of these extracellular "cytokine" PGI/AMF can be seen.  The amount of PGI/AMF that is secreted inside and outside the cell based on infection <ref> Funasaka T, Hu H, Yanagawa T, Hogan V, Raz A. Down-Regulation of Phosphoglucose Isomerase/Autocrine Motility Factors Results in Mesenchymal-to-Epithelial Transition of Human Lung Fibrosarcoma Cells. (2007) Cancer Res, 76(9) </ref>.   
'''Inhibition'''    of the phosphoglucoisomerase regulated reaction of glucose-6-phosphate to fructose-6-phosphate can also occur.  Competitive competition can take place from inhibitors such as 5PAH.  5PAH resembles PGI, differing only in a nitrogen atom at the first carbon position.  5PAH is reported to have a Ki of .0000002 M <ref> Arsenieva D, Hardre R, Salmon L, Jeffery CJ.  The crystal structure of rabbit phosphoglucose isomerase complex with 5-phospho-D-arabinonohydroxamic acid. (2002),PNAS, 99(9) </ref>.
=='''Links'''==
=='''Links'''==


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* Other available structures [[1dqr]], [[1g98]], [[1gzd]], [[1gzv]], [[1hm5]], [[1iri]], [[1jiq]], [[1jlh]], [[1koj]], [[1n8t]], [[1nuh]], [[1xtb]].
* Other available structures [[1dqr]], [[1g98]], [[1gzd]], [[1gzv]], [[1hm5]], [[1iri]], [[1jiq]], [[1jlh]], [[1koj]], [[1n8t]], [[1nuh]], [[1xtb]].


=='''References'''==
==3D structures of phosphoglucose isomerase==
 
===PGI===
 
[[2pgi]], [[1b0z]] – GsPGI – ''Geobacillus stearothermophilus''<br />
[[1dqr]], [[1hm5]], [[1n8t]] – rPGI – rabbit<br />
[[1iat]], [[1jlh]] – hPGI – human<br />
[[1qxj]], [[1x8e]], [[3sxw]] – PfPGI – ''Pyrococcus furiosus''<br />
[[1j3p]], [[1j3q]] – TlPGI – ''Thermococcus litoralis''<br />
[[1q50]] – LmPGI – ''Leishmania Mexicana''<br />
[[1u0e]], [[2cvp]] – mPGI – mouse<br />
[[2q8n]] – PGI – ''Thermotoga maritima''<br />
[[3hjb]] – PGI – ''Vibrio cholera''<br />
[[3ifs]] – PGI – ''Bacillus anthracis''<br />
[[2wu8]] – PGI – ''Mycobacterium tuberculosis''<br />
[[3ljk]] – FtPGI (mutant) – ''Francisella tularensis''<br />
[[3nbu]] – PGI – ''Escherichia coli''
 
===PGI complex with fructose-6-phosphate===
 
[[1hox]] – rPGI + fructose-6-phosphate<br />
[[1t10]] - LmPGI + fructose-6-phosphate<br />
[[2gc2]] - PfPGI + fructose-6-phosphate<br />
[[2cxs]], [[2cxt]] - mPGI + fructose-6-phosphate<br />
[[3m5p]] - FtPGI (mutant) + fructose-6-phosphate<br />
 
===PGI complex with sorbitol-6-phosphate===
 
[[1xtb]] - rPGI + sorbitol-6-phosphate<br />
[[2gc1]] - PfPGI + sorbitol-6-phosphate<br />
[[2cxq]] - mPGI + sorbitol-6-phosphate<br />
 
===PGI complex with phosphoarabinose===
 
[[1gzd]], [[1gzv]] – PGI + phosphoarabinose – pig<br />
[[1c7r]] - GsPGI + phosphoarabinose<br />
[[2cxp]] – mPGI + phosphoarabinose<br />
[[1nuh]] - hPGI + phosphoarabinose<br />
[[1qsr]], [[1x7n]], [[1x82]] - PfPGI + phosphoarabinose<br />
[[2gc0]] - PfPGI + phosphoarabinose derivative<br />
[[1koj]] – rPGI + phosphoarabinose derivative
 
===PGI complex with gluconate-6-phosphate===
 
[[1qy4]] - PfPGI + gluconate-6-phosphate<br />
[[1j3r]] - TlPGI + gluconate-6-phosphate<br />
[[2cxr]] - mPGI + gluconate-6-phosphate<br />
[[3q7i]] - FtPGI (mutant) + gluconate-6-phosphate<br />
 
===PGI complex with glucose-6-phosphate===
 
[[1u0f]] - mPGI + glucose-6-phosphate<br />
[[3ff1]] - PGI + glucose-6-phosphate – ''Staphylococcus aureus''<br />
[[2o2c]] - TbPGI + glucose-6-phosphate – ''Trypanosoma brucei''
 
===Other PGI binary complexes===
 
[[2o2d]] – TbPGI + citrate<br />
[[1u0g]], [[2cxo]] - mPGI + erythrose-4-phosphate<br />
[[3q88]] – FtPGI (mutant) + ribose bisphosphate<br />
[[1c7q]] – GsPGI + phosphate inhibitor<br />
[[2cxn]], [[2cxu]] – mPGI + phosphate<br />
[[1g98]] – rPGI + transition state analog<br />
[[2gc3]] - PfPGI + mannose-6-phosphate<br />
 
==Additional Resources==
For additional information, see: [[Carbohydrate Metabolism]]
<br />
 
==References==
<references/>
<references/>
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