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" protrusions.
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 that 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 hemolytic anemia and a severe enzyme deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment.
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.
Neuroleukin also acts as a lymphokine secreted by T cells stimulated by lectin. It induces immunoglobulin secretion in B cells as part of a response that activates antibody-secreting cells.
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.
^ abJeffery 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". Biochemistry39 (5): 955–64. doi:10.1021/bi991604m. PMID10653639.
^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. PMID11371164.
^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. PMID15342241.
^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. PMID17029220.
^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". Nature332 (6163): 454–5. doi:10.1038/332454a0. PMID3352744.
^Gurney ME, Heinrich SP, Lee MR, Yin HS (October 1986). "Molecular cloning and expression of neuroleukin, a neurotrophic factor for spinal and sensory neurons". Science234 (4776): 566–74. doi:10.1126/science.3764429. PMID3764429.
^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". Science234 (4776): 574–81. doi:10.1126/science.3020690. PMID3020690.
^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. PMID15252053.
^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. PMID8499925.
^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". Blood88 (6): 2321–5. PMID8822954.
Brownstein BH, Silverman GA, Little RD, et al. (1989). "Isolation of single-copy human genes from a library of yeast artificial chromosome clones.". Science244 (4910): 1348–51. doi:10.1126/science.2544027. PMID2544027.
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. PMID2547084.
Faik P, Walker JI, Redmill AA, Morgan MJ (1988). "Mouse glucose-6-phosphate isomerase and neuroleukin have identical 3' sequences.". Nature332 (6163): 455–7. doi:10.1038/332455a0. PMID3352745.
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. PMID7435496.
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.". Genomics21 (1): 122–7. doi:10.1006/geno.1994.1233. PMID7545951.
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.". Blood88 (6): 2306–10. PMID8822952.
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. PMID9446754.
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. PMID9616041.
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. PMID9856489.
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.". Gene230 (2): 259–66. doi:10.1016/S0378-1119(99)00056-6. PMID10216265.
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. PMID10727272.
Haga A, Niinaka Y, Raz A (2000). "Phosphohexose isomerase/autocrine motility factor/neuroleukin/maturation factor is a multifunctional phosphoprotein.". Biochim. Biophys. Acta1480 (1-2): 235–44. doi:10.1016/s0167-4838(00)00075-3. PMID11004567.