Summary: Phosphoglucose isomerase
This is the Wikipedia entry entitled "Glucose-6-phosphate isomerase". More...
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Glucose-6-phosphate isomerase Edit Wikipedia article
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
|Bacterial phospho-glucose isomerase C-terminal region|
crystal structure of phosphoglucose/phosphomannose isomerase from pyrobaculum aerophilum in complex with fructose 6-phosphate
PDB rendering based on 1dqr.
|RNA expression pattern|
Glucose-6-phosphate isomerase (alternatively known as phosphoglucose isomerase or phosphohexose isomerase) is an enzyme that catalyzes the conversion of glucose-6-phosphate into fructose 6-phosphate in the second step of glycolysis.
PGI monomers are made of two domains, one made of two separate segments called the large domain and the other made of the segment in between called the small domain. The two domains are each αβα sandwiches, with the small domain containing a five-strand β-sheet surrounded by α-helices while the large domain has a six-stranded β-sheet. The large domain and the C-terminal of each monomer also contain "arm-like" protruisions.
Functional PGI is a dimer composed of two identical monomers. The two monomers interact notably through the two protrusions in a hugging embrace. The active site of each monomer is formed by a cleft between the two domains and the dimer interface.
The mechanism for PGI uses to interconvert glucose 6-phosphate and fructose 6-phosphate consists of three major steps: opening the glucose ring, isomerizing glucose into fructose through an enediol intermediate, and closing the fructose ring.
Glucose 6 phosphate binds to PGI as a hemiacetal ring. The ring is opened in a "push-pull" mechanism by His388, which protonates the C5 oxygen, and Lys518, which deprotonates the C1 hydroxyl group. This creates an open chain aldose. Then, the substrated is rotated about the C3-C4 bond to position it for isomerization. At this point, Glu357 deprotonates C2 to create a cis-enediolate intermediate stabilized by Arg272. To complete the isomerization, Glu357 donates its proton to C1, the C2 hydroxyl group loses its proton and the open-chain ketose, Fructose 6-phosphate is formed. Finally, the ring is closed by rotating the substrate about the C3-C4 bond again and deptrotonating the C5 hydroxyl with Lys518 to cause to the opposite of the ring opening mechanism used to start the reaction.
This gene belongs to the GPI family whose members encode multifunctional phosphoglucose isomerase proteins involved in energy pathways. The protein encoded by this gene is a dimeric enzyme that catalyzes the reversible isomerization of glucose-6-phosphate and fructose-6-phosphate.
The protein has different functions inside and outside the cell. In the cytoplasm, the protein is involved in glycolysis and gluconeogenesis, while outside the cell it functions as a neurotrophic factor for spinal and sensory neurons. The same protein is also secreted by cancer cells, where it is called autocrine motility factor and stimulates metastasis. Defects in this gene are the cause of nonspherocytic and a severe enzyme deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment.
|α-D-Glucose 6-phosphate||Phosphoglucose isomerase||β-D-Fructose 6-phosphate|
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".
Isomerization of glucose
Though originally treated as separate proteins, cloning technology demonstrated that PGI is almost identical to the protein neuroleukin. Neuroleukin is a neurotrophic factor for spinal and sensory neurons. It is found in large amounts in muscle, brain, heart, and kidneys.
Tumor Cell Autocrine Motility Factor
Cloning experiments also revealed that PGI is identical to the protein known as autocrine motility factor. Autocrine motility factor produced and secreted by cancer cells and stimulates cell growth and motility as a growth factor. Autocrine motility factor is thought to play a key role in cancer metastasis.
Prokaryotic bifunctional glucose-6-phosphate isomerase
In some archaea and bacteria glucose-6-phosphate isomerase (PGI) activity occurs via a bifunctional enzyme that also exhibits phosphomannose isomerase (PMI) activity. Though not closely related to eukaryotic PGIs, the bifunctional enzyme is similar enough that the sequence includes the cluster of threonines and serines that forms the sugar phosphate-binding site in conventional PGI. The enzyme is thought to use the same catalytic mechanisms for both glucose ring-opening and isomerisation for the interconversion of glucose 6-phosphate to fructose 6-phosphate.
Several cases of glucose phosphate isomerase deficiency have recently been identified.
- Graham Solomons JT, Zimmerly EM, Burns S, Krishnamurthy N, Swan MK, Krings S, Muirhead H, Chirgwin J, Davies C (September 2004). "The crystal structure of mouse phosphoglucose isomerase at 1.6A resolution and its complex with glucose 6-phosphate reveals the catalytic mechanism of sugar ring opening". J Mol Biol. 342 (3): 847–60. doi:10.1016/j.jmb.2004.07.085. PMID 15342241.
- "Entrez Gene: GPI glucose phosphate isomerase".
- Sun YJ, Chou CC, Chen WS, Wu RT, Meng M, Hsiao CD (May 1999). "The crystal structure of a multifunctional protein: phosphoglucose isomerase/autocrine motility factor/neuroleukin". Proc Natl Acad Sci U S A 96 (10): 5412–5417. PMC 21873. PMID 10318897.
- Jeffery CJ, Bahnson BJ, Chien W, Ringe D, Petsko GA (February 2000). "Crystal structure of rabbit phosphoglucose isomerase, a glycolytic enzyme that moonlights as neuroleukin, autocrine motility factor, and differentiation mediator". Biochemistry 39 (5): 955–64. doi:10.1021/bi991604m. PMID 10653639.
- Read J, Pearce J, Li X, Muirhead H, Chirgwin J, Davies C (June 2001). "The crystal structure of human phosphoglucose isomerase at 1.6 A resolution: implications for catalytic mechanism, cytokine activity and haemolytic anaemia". J Mol Biol. 309 (2): 447–63. doi:10.1006/jmbi.2001.4680. PMID 11371164.
- Dobashi Y, Watanabe H, Sato Y, et al. (December 2006). "Differential expression and pathological significance of autocrine motility factor/glucose-6-phosphate isomerase expression in human lung carcinomas". J. Pathol. 210 (4): 431–40. doi:10.1002/path.2069. PMID 17029220.
- Watanabe H, Takehana K, Date M, Shinozaki T, Raz A (1 July 1996). "Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide". Cancer Res. 56 (13): 2960–3. PMID 8674049.
- Chaput M, Claes V, Portetelle D, Cludts I, Cravador A, Burny A, Gras H, Tartar A (March 1988). "The neurotrophic factor neuroleukin is 90% homologous with phosphohexose isomerase". Nature 332 (6163): 454–5. doi:10.1038/332454a0. PMID 3352744.
- Gurney ME, Heinrich SP, Lee MR, Yin HS (October 1986). "Molecular cloning and expression of neuroleukin, a neurotrophic factor for spinal and sensory neurons". Science 234 (4776): 566–74. doi:10.1126/science.3764429. PMID 3764429.
- Gurney ME, Apatoff BR, Spear GT, Baumel MJ, Antel JP, Bania MB, Reder AT (October 1986). "Neuroleukin: a lymphokine product of lectin-stimulated T cells". Science 234 (4776): 574–81. doi:10.1126/science.3020690. PMID 3020690.
- Watanabe H, Takehana K, Date M, Shinozaki T, Raz A (July 1996). "Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide". Cancer Res. 56 (13): 2960–3. PMID 8674049.
- Silletti S, Raz A (July 1993). "Autocrine motility factor is a growth factor". Biochem Biophys Res Commun. 194 (1): 454–5. doi:10.1006/bbrc.1993.1840. PMID 8392842.
- Liotta LA, Mandler R, Murano G, Katz DA, Gordon RK, Chiang PK, Schiffmann E (May 1986). "Tumor cell autocrine motility factor". Proc Natl Acad Sci U S A 83 (10): 3302–6. PMID 3085086.
- Swan MK, Hansen T, Schonheit P, Davies C (September 2004). "A novel phosphoglucose isomerase (PGI)/phosphomannose isomerase from the crenarchaeon Pyrobaculum aerophilum is a member of the PGI superfamily: structural evidence at 1.16-A resolution". J. Biol. Chem. 279 (38): 39838–45. doi:10.1074/jbc.M406855200. PMID 15252053.
- Walker JI, Layton DM, Bellingham AJ, Morgan MJ, Faik P (March 1993). "DNA sequence abnormalities in human glucose 6-phosphate isomerase deficiency". Hum. Mol. Genet. 2 (3): 327–9. doi:10.1093/hmg/2.3.327. PMID 8499925.
- Kanno H, Fujii H, Hirono A, Ishida Y, Ohga S, Fukumoto Y, Matsuzawa K, Ogawa S, Miwa S (September 1996). "Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia". Blood 88 (6): 2321–5. PMID 8822954.
- Kugler W, Lakomek M (March 2000). "Glucose-6-phosphate isomerase deficiency". Baillieres Best Pract. Res. Clin. Haematol. 13 (1): 89–101. PMID 10916680.
- "GPI Deficiency".
- Walker JI, Faik P, Morgan MJ (1990). "Characterization of the 5' end of the gene for human glucose phosphate isomerase (GPI).". Genomics 7 (4): 638–43. doi:10.1016/0888-7543(90)90212-D. PMID 2387591.
- Brownstein BH, Silverman GA, Little RD, et al. (1989). "Isolation of single-copy human genes from a library of yeast artificial chromosome clones.". Science 244 (4910): 1348–51. doi:10.1126/science.2544027. PMID 2544027.
- Mizrachi Y (1989). "Neurotrophic activity of monomeric glucophosphoisomerase was blocked by human immunodeficiency virus (HIV-1) and peptides from HIV-1 envelope glycoprotein.". J. Neurosci. Res. 23 (2): 217–24. doi:10.1002/jnr.490230212. PMID 2547084.
- Gurney ME, Apatoff BR, Spear GT, et al. (1986). "Neuroleukin: a lymphokine product of lectin-stimulated T cells.". Science 234 (4776): 574–81. doi:10.1126/science.3020690. PMID 3020690.
- Faik P, Walker JI, Redmill AA, Morgan MJ (1988). "Mouse glucose-6-phosphate isomerase and neuroleukin have identical 3' sequences.". Nature 332 (6163): 455–7. doi:10.1038/332455a0. PMID 3352745.
- Zanella A, Izzo C, Rebulla P, et al. (1981). "The first stable variant of erythrocyte glucose-phosphate isomerase associated with severe hemolytic anemia.". Am. J. Hematol. 9 (1): 1–11. doi:10.1002/ajh.2830090102. PMID 7435496.
- Faik P, Walker JI, Morgan MJ (1994). "Identification of a novel tandemly repeated sequence present in an intron of the glucose phosphate isomerase (GPI) gene in mouse and man.". Genomics 21 (1): 122–7. doi:10.1006/geno.1994.1233. PMID 7545951.
- Xu W, Beutler E (1995). "The characterization of gene mutations for human glucose phosphate isomerase deficiency associated with chronic hemolytic anemia.". J. Clin. Invest. 94 (6): 2326–9. doi:10.1172/JCI117597. PMC 330061. PMID 7989588.
- Xu W, Lee P, Beutler E (1996). "Human glucose phosphate isomerase: exon mapping and gene structure.". Genomics 29 (3): 732–9. doi:10.1006/geno.1995.9944. PMID 8575767.
- Baronciani L, Zanella A, Bianchi P, et al. (1996). "Study of the molecular defects in glucose phosphate isomerase-deficient patients affected by chronic hemolytic anemia.". Blood 88 (6): 2306–10. PMID 8822952.
- Beutler E, West C, Britton HA, et al. (1998). "Glucosephosphate isomerase (GPI) deficiency mutations associated with hereditary nonspherocytic hemolytic anemia (HNSHA).". Blood Cells Mol. Dis. 23 (3): 402–9. doi:10.1006/bcmd.1997.0157. PMID 9446754.
- Kanno H, Fujii H, Miwa S (1998). "Expression and enzymatic characterization of human glucose phosphate isomerase (GPI) variants accounting for GPI deficiency.". Blood Cells Mol. Dis. 24 (1): 54–61. doi:10.1006/bcmd.1998.0170. PMID 9616041.
- Kugler W, Breme K, Laspe P, et al. (1998). "Molecular basis of neurological dysfunction coupled with haemolytic anaemia in human glucose-6-phosphate isomerase (GPI) deficiency.". Hum. Genet. 103 (4): 450–4. doi:10.1007/s004390050849. PMID 9856489.
- Belyaeva OV, Balanovsky OP, Ashworth LK, et al. (1999). "Fine mapping of a polymorphic CA repeat marker on human chromosome 19 and its use in population studies.". Gene 230 (2): 259–66. doi:10.1016/S0378-1119(99)00056-6. PMID 10216265.
- Yakirevich E, Naot Y (2000). "Cloning of a glucose phosphate isomerase/neuroleukin-like sperm antigen involved in sperm agglutination.". Biol. Reprod. 62 (4): 1016–23. doi:10.1095/biolreprod62.4.1016. PMID 10727272.
- Haga A, Niinaka Y, Raz A (2000). "Phosphohexose isomerase/autocrine motility factor/neuroleukin/maturation factor is a multifunctional phosphoprotein.". Biochim. Biophys. Acta 1480 (1-2): 235–44. PMID 11004567.
- Glucose-6-phosphate isomerase in PROSITE
- Phosphoglucose Isomerase
- Glucose phosphate isomerase deficiency
|Glycolysis Metabolic Pathway|
Phosphoglucose isomerase Provide feedback
Phosphoglucose isomerase catalyses the interconversion of glucose-6-phosphate and fructose-6-phosphate.
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001672
Phosphoglucose isomerase (EC) (PGI) [PUBMED:6115414, PUBMED:1593646] is a dimeric enzyme that catalyses the reversible isomerization of glucose-6-phosphate and fructose-6-phosphate. PGI is involved in different pathways: in most higher organisms it is involved in glycolysis; in mammals it is involved in gluconeogenesis; in plants in carbohydrate biosynthesis; in some bacteria it provides a gateway for fructose into the Entner-Doudouroff pathway. The multifunctional protein, PGI, is also known as neuroleukin (a neurotrophic factor that mediates the differentiation of neurons), autocrine motility factor (a tumour-secreted cytokine that regulates cell motility), differentiation and maturation mediator and myofibril-bound serine proteinase inhibitor, and has different roles inside and outside the cell. In the cytoplasm, it catalyses the second step in glycolysis, while outside the cell it serves as a nerve growth factor and cytokine [PUBMED:10653639].
PGI from Bacillus stearothermophilus has an open twisted alpha/beta structural motif consisting of two globular domains and two protruding parts. It has been suggested that the top part of the large domain together with one of the protruding loops might participate in inducing the neurotrophic activity [PUBMED:10318897]. The structure of rabbit muscle phosphoglucose isomerase complexed with various inhibitors shows that the enzyme is a dimer with two alpha/beta-sandwich domains in each subunit. The location of the bound D-gluconate 6-phosphate inhibitor leads to the identification of residues involved in substrate specificity. In addition, the positions of amino acid residues that are substituted in the genetic disease nonspherocytic hemolytic anemia suggest how these substitutions can result in altered catalysis or protein stability [PUBMED:10653639, PUBMED:10770936].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||glucose-6-phosphate isomerase activity (GO:0004347)|
|Biological process||gluconeogenesis (GO:0006094)|
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|Author:||Bateman A, Finn RD|
|Number in seed:||10|
|Number in full:||7325|
|Average length of the domain:||366.00 aa|
|Average identity of full alignment:||35 %|
|Average coverage of the sequence by the domain:||89.39 %|
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build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||14|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the PGI domain has been found. There are 105 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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