glucose 6 phosphate isomerase


Summary: An aldose-ketose isomerase that catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate. In prokaryotic and eukaryotic organisms it plays an essential role in glycolytic and gluconeogenic pathways. In mammalian systems the enzyme is found in the cytoplasm and as a secreted protein. This secreted form of glucose-6-phosphate isomerase has been referred to as autocrine motility factor or neuroleukin, and acts as a cytokine which binds to the AUTOCRINE MOTILITY FACTOR RECEPTOR. Deficiency of the enzyme in humans is an autosomal recessive trait, which results in CONGENITAL NONSPHEROCYTIC HEMOLYTIC ANEMIA.

Top Publications

  1. Yanagawa T, Funasaka T, Tsutsumi S, Raz T, Tanaka N, Raz A. Differential regulation of phosphoglucose isomerase/autocrine motility factor activities by protein kinase CK2 phosphorylation. J Biol Chem. 2005;280:10419-26 pubmed
    ..The process by which phosphorylation modulates the enzymatic activity of PGI thus has an important implication for the understanding of the biological regulation of this key glucose metabolism-regulating enzyme. ..
  2. van Gaalen F, Toes R, Ditzel H, Schaller M, Breedveld F, Verweij C, et al. Association of autoantibodies to glucose-6-phosphate isomerase with extraarticular complications in rheumatoid arthritis. Arthritis Rheum. 2004;50:395-9 pubmed
    ..In patients with RA, autoantibodies to GPI are associated with the occurrence of extraarticular complications. ..
  3. Yanagawa T, Watanabe H, Takeuchi T, Fujimoto S, Kurihara H, Takagishi K. Overexpression of autocrine motility factor in metastatic tumor cells: possible association with augmented expression of KIF3A and GDI-beta. Lab Invest. 2004;84:513-22 pubmed
    ..The RNA message and protein expression of these two molecules was confirmed to be upregulated, suggesting a possible association with AMF-induced signaling for cell motility and metastasis. ..
  4. Maccioni M, Zeder Lutz G, Huang H, Ebel C, Gerber P, Hergueux J, et al. Arthritogenic monoclonal antibodies from K/BxN mice. J Exp Med. 2002;195:1071-7 pubmed
    ..These results confirm that GPI itself, rather than a cross-reactive molecule, is the target of pathogenic Igs. ..
  5. Solomon S, Kolb C, Mohanty S, Jeisy Walder E, Preyer R, Schöllhorn V, et al. Transmission of antibody-induced arthritis is independent of complement component 4 (C4) and the complement receptors 1 and 2 (CD21/35). Eur J Immunol. 2002;32:644-51 pubmed
    ..The crucial role of complement C5, while neither classical nor lectin pathway is necessary, indicates that the alternative complement pathway may have a role in the K/BxN serum-induced RA model. ..
  6. Tsutsumi S, Yanagawa T, Shimura T, Fukumori T, Hogan V, Kuwano H, et al. Regulation of cell proliferation by autocrine motility factor/phosphoglucose isomerase signaling. J Biol Chem. 2003;278:32165-72 pubmed
  7. Xu W, Seiter K, Feldman E, Ahmed T, Chiao J. The differentiation and maturation mediator for human myeloid leukemia cells shares homology with neuroleukin or phosphoglucose isomerase. Blood. 1996;87:4502-6 pubmed
    ..Whether they represent an excess of the differentiation regulator in patients and are important in leukemogenesis remain to be investigated. ..
  8. Dobashi Y, Watanabe H, Sato Y, Hirashima S, Yanagawa T, Matsubara H, et al. Differential expression and pathological significance of autocrine motility factor/glucose-6-phosphate isomerase expression in human lung carcinomas. J Pathol. 2006;210:431-40 pubmed
    ..Furthermore, higher mRNA expression may be related to the high metastatic potential of NSCLC and increased protein secretion, leading to a more aggressive phenotype, such as the invasiveness of SmCC and LCC. ..
  9. Chou C, Sun Y, Meng M, Hsiao C. The crystal structure of phosphoglucose isomerase/autocrine motility factor/neuroleukin complexed with its carbohydrate phosphate inhibitors suggests its substrate/receptor recognition. J Biol Chem. 2000;275:23154-60 pubmed
    ..Based on these two complex structures, together with biological and biochemical results, we propose a possible isomerization mechanism for phosphoglucose isomerase. ..

More Information


  1. Jeffery C, Bahnson B, Chien W, Ringe D, Petsko G. Crystal structure of rabbit phosphoglucose isomerase, a glycolytic enzyme that moonlights as neuroleukin, autocrine motility factor, and differentiation mediator. Biochemistry. 2000;39:955-64 pubmed
    ..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...
  2. Wipke B, Wang Z, Kim J, McCarthy T, Allen P. Dynamic visualization of a joint-specific autoimmune response through positron emission tomography. Nat Immunol. 2002;3:366-72 pubmed
    ..The rapid kinetics of anti-GPI IgG joint localization supports a model in which autoantibodies bind directly to pre-existing extracellular GPI in normal healthy mouse joints...
  3. Studelska D, Mandik Nayak L, Zhou X, Pan J, Weiser P, McDowell L, et al. High affinity glycosaminoglycan and autoantigen interaction explains joint specificity in a mouse model of rheumatoid arthritis. J Biol Chem. 2009;284:2354-62 pubmed publisher
    ..Our studies raise the possibility that GAGs are the receptors for other autoantigens involved in joint-specific inflammatory responses. ..
  4. Wheat C, Watt W, Pollock D, Schulte P. From DNA to fitness differences: sequences and structures of adaptive variants of Colias phosphoglucose isomerase (PGI). Mol Biol Evol. 2006;23:499-512 pubmed
    ..This study provides novel views of molecular-structural mechanisms, and beginnings of historical evidence, for a long-persistent balanced enzyme polymorphism at PGI in these and perhaps other species. ..
  5. Matsumoto I, Zhang H, Yasukochi T, Iwanami K, Tanaka Y, Inoue A, et al. Therapeutic effects of antibodies to tumor necrosis factor-alpha, interleukin-6 and cytotoxic T-lymphocyte antigen 4 immunoglobulin in mice with glucose-6-phosphate isomerase induced arthritis. Arthritis Res Ther. 2008;10:R66 pubmed publisher
  6. Torimura T, Ueno T, Kin M, Harada R, Nakamura T, Kawaguchi T, et al. Autocrine motility factor enhances hepatoma cell invasion across the basement membrane through activation of beta1 integrins. Hepatology. 2001;34:62-71 pubmed
    ..Our results indicate that AMF/PHI enhances hepatoma cell invasion through Matrigel in an autocrine manner by stimulating the adhesion, motility, and MMP-2 secretion of these cells through activation of beta1 integrins. ..
  7. Mishra S, Raz A, Murphy L. Insulin-like growth factor binding protein-3 interacts with autocrine motility factor/phosphoglucose isomerase (AMF/PGI) and inhibits the AMF/PGI function. Cancer Res. 2004;64:2516-22 pubmed
    ..The ability of IGFBP-3 to bind and inhibit the actions of AMF/PGI may have some role in the antiproliferative proapoptotic effects of IGFBP-3. ..
  8. Watanabe H, Takehana K, Date M, Shinozaki T, Raz A. Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide. Cancer Res. 1996;56:2960-3 pubmed
    ..Specific PHI inhibitors (carbohydrate phosphates) inhibited enzymatic activity and AMF-induced cell motility. ..
  9. Muraki Y, Matsumoto I, Chino Y, Hayashi T, Suzuki E, Goto D, et al. Glucose-6-phosphate isomerase variants play a key role in the generation of anti-GPI antibodies: possible mechanism of autoantibody production. Biochem Biophys Res Commun. 2004;323:518-22 pubmed
    ..6%) was more significantly higher than in anti-GPI Ab-negative patients (1/63, 1.6%, p < 0.0001). Our results suggest that GPI variants may play a crucial role in the production of autoantibodies against ubiquitous GPI autoantigens. ..
  10. Sun Y, Chou C, Chen W, Wu R, Meng M, Hsiao C. The crystal structure of a multifunctional protein: phosphoglucose isomerase/autocrine motility factor/neuroleukin. Proc Natl Acad Sci U S A. 1999;96:5412-7 pubmed
    ..In addition, the structure provides evidence suggesting that the top part of the large domain together with one of the protruding loops might participate in inducing the neurotrophic activity. ..
  11. Iwanami K, Matsumoto I, Tanaka Watanabe Y, Inoue A, Mihara M, Ohsugi Y, et al. Crucial role of the interleukin-6/interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase. Arthritis Rheum. 2008;58:754-63 pubmed publisher
  12. Rank N, Bruce D, McMillan D, Barclay C, Dahlhoff E. Phosphoglucose isomerase genotype affects running speed and heat shock protein expression after exposure to extreme temperatures in a montane willow beetle. J Exp Biol. 2007;210:750-64 pubmed
  13. Mandik Nayak L, Wipke B, Shih F, Unanue E, Allen P. Despite ubiquitous autoantigen expression, arthritogenic autoantibody response initiates in the local lymph node. Proc Natl Acad Sci U S A. 2002;99:14368-73 pubmed
    ..These findings imply that the immune physiology of a joint is unique, resulting in a local immune response to a systemic autoantigen. ..
  14. Watt W, Wheat C, Meyer E, Martin J. Adaptation at specific loci. VII. Natural selection, dispersal and the diversity of molecular-functional variation patterns among butterfly species complexes (Colias: Lepidoptera, Pieridae). Mol Ecol. 2003;12:1265-75 pubmed
    ..This case offers new opportunities for integrating studies of molecular structure and function with ecological aspects of natural selection in the wild, both within and among species. ..
  15. Schubert D, Maier B, Morawietz L, Krenn V, Kamradt T. Immunization with glucose-6-phosphate isomerase induces T cell-dependent peripheral polyarthritis in genetically unaltered mice. J Immunol. 2004;172:4503-9 pubmed
    ..Both the induction and effector phase of arthritis induced by a systemic autoimmune response can be dissected and preventive and therapeutic strategies evaluated in this model. ..
  16. West J, Flockhart J, Peters J, Ball S. Death of mouse embryos that lack a functional gene for glucose phosphate isomerase. Genet Res. 1990;56:223-36 pubmed
    ..The morphological similarity between homozygous nulls and androgenetic conceptuses, where the trophoblast also survives better than the embryo, is discussed. ..
  17. Chaput M, Claes V, Portetelle D, Cludts I, Cravador A, Burny A, et al. The neurotrophic factor neuroleukin is 90% homologous with phosphohexose isomerase. Nature. 1988;332:454-5 pubmed
    ..3.1.9) which catalyses the conversion of glucose-6-phosphate to fructose-6-phosphate, an obligatory step in glycolysis, and determined its amino-acid sequence. Surprisingly, it is 90% homologous to the sequence of mouse neuroleukin. ..
  18. Niizeki H, Kobayashi M, Horiuchi I, Akakura N, Chen J, Wang J, et al. Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells. Br J Cancer. 2002;86:1914-9 pubmed
  19. Schubert D, Schmidt M, Zaiss D, Jungblut P, Kamradt T. Autoantibodies to GPI and creatine kinase in RA. Nat Immunol. 2002;3:411; author reply 412-3 pubmed
  20. Kao H, Lee S. Phosphoglucose isomerases of hagfish, zebrafish, gray mullet, toad, and snake, with reference to the evolution of the genes in vertebrates. Mol Biol Evol. 2002;19:367-74 pubmed
    ..The gene tree suggests that the gene duplication event of PGI in bonyfishes occurred before diversification of Acanthopterygii but after the split of bonyfishes and tetrapods. The evolution of multiple functions of PGI is discussed. ..
  21. Orsini L, Wheat C, Haag C, Kvist J, Frilander M, Hanski I. Fitness differences associated with Pgi SNP genotypes in the Glanville fritillary butterfly (Melitaea cinxia). J Evol Biol. 2009;22:367-75 pubmed publisher
    ..Although this is consistent with direct overdominance at Pgi, we cannot exclude the possibility that heterozygote advantage is caused by the presence of one or more deleterious alleles at linked loci. ..
  22. Dahlhoff E, Rank N. Functional and physiological consequences of genetic variation at phosphoglucose isomerase: heat shock protein expression is related to enzyme genotype in a montane beetle. Proc Natl Acad Sci U S A. 2000;97:10056-61 pubmed
    ..These results reveal functional and physiological differences among PGI genotypes, which suggest that montane populations of this beetle are locally adapted to temperature. ..
  23. Cha H, Kim T, Kim J, Lee M, Jeon C, Kim J, et al. Autoantibodies to glucose-6-phosphate isomerase are elevated in the synovial fluid of rheumatoid arthritis patients. Scand J Rheumatol. 2004;33:179-84 pubmed
    ..Our study indicates that anti-GPI antibody in the synovial fluid is specifically related to RA, and suggests that GPI and its autoantibody might be important in the pathogenesis of human RA. ..
  24. Bockermann R, Schubert D, Kamradt T, Holmdahl R. Induction of a B-cell-dependent chronic arthritis with glucose-6-phosphate isomerase. Arthritis Res Ther. 2005;7:R1316-24 pubmed
    ..We conclude that G6PI has the ability to induce a chronic arthritis, which is MHC associated and B-cell dependent. Thus, there are striking similarities between this and the collagen-induced arthritis model. ..
  25. Katz L, Harrison R. Balancing selection on electrophoretic variation of phosphoglucose isomerase in two species of field cricket: Gryllus veletis and G. offnsylvanicus. Genetics. 1997;147:609-21 pubmed
    ..Instead, the data are consistent with balancing selection operating on an emergent property of the PGI protein. ..
  26. Niinaka Y, Paku S, Haga A, Watanabe H, Raz A. Expression and secretion of neuroleukin/phosphohexose isomerase/maturation factor as autocrine motility factor by tumor cells. Cancer Res. 1998;58:2667-74 pubmed
  27. Yanagawa T, Funasaka T, Tsutsumi S, Hu H, Watanabe H, Raz A. Regulation of phosphoglucose isomerase/autocrine motility factor activities by the poly(ADP-ribose) polymerase family-14. Cancer Res. 2007;67:8682-9 pubmed
  28. Tsutsumi S, Hogan V, Nabi I, Raz A. Overexpression of the autocrine motility factor/phosphoglucose isomerase induces transformation and survival of NIH-3T3 fibroblasts. Cancer Res. 2003;63:242-9 pubmed
    ..Overexpression of this housekeeping gene induces resistance to apoptosis and neoplastic transformation, and, thus, AMF/PGI represents a novel class of oncogenic protein. ..
  29. Funasaka T, Hu H, Yanagawa T, Hogan V, Raz A. Down-regulation of phosphoglucose isomerase/autocrine motility factor results in mesenchymal-to-epithelial transition of human lung fibrosarcoma cells. Cancer Res. 2007;67:4236-43 pubmed
  30. Tanaka Watanabe Y, Matsumoto I, Iwanami K, Inoue A, Goto D, Ito S, et al. B cells play a crucial role as antigen-presenting cells and collaborate with inflammatory cytokines in glucose-6-phosphate isomerase-induced arthritis. Clin Exp Immunol. 2009;155:285-94 pubmed publisher
    ..Our results highlight the important role of B cells in GPI-induced arthritis as autoantibody producers, and these autoantibodies can trigger joint inflammation in orchestration with inflammatory cytokines, especially TNF-alpha...
  31. Kori Y, Matsumoto I, Zhang H, Yasukochi T, Hayashi T, Iwanami K, et al. Characterisation of Th1/Th2 type, glucose-6-phosphate isomerase reactive T cells in the generation of rheumatoid arthritis. Ann Rheum Dis. 2006;65:968-9 pubmed
  32. Huang H, Kearney J, Grusby M, Benoist C, Mathis D. Induction of tolerance in arthritogenic B cells with receptors of differing affinity for self-antigen. Proc Natl Acad Sci U S A. 2006;103:3734-9 pubmed
    ..These studies portray, in a single system, the range of tolerance mechanisms applied to potentially pathogenic B cells, and serve as a base for dissecting where T cell help intervenes and where therapeutic agents impinge. ..
  33. Schmitt A, Schubert D, Sengler C, Kamradt T. Autoantibodies against glucose-6-phosphate isomerase are not a diagnostic marker for juvenile idiopathic arthritis. Ann Rheum Dis. 2004;63:463 pubmed
  34. Sato J, Yanagawa T, Dobashi Y, Yamaji T, Takagishi K, Watanabe H. Prognostic significance of 18F-FDG uptake in primary osteosarcoma after but not before chemotherapy: a possible association with autocrine motility factor/phosphoglucose isomerase expression. Clin Exp Metastasis. 2008;25:427-35 pubmed publisher
  35. Yanagawa T, Funasaka T, Tsutsumi S, Watanabe H, Raz A. Novel roles of the autocrine motility factor/phosphoglucose isomerase in tumor malignancy. Endocr Relat Cancer. 2004;11:749-59 pubmed
    ..These novel functions of AMF makes it a likely target for cancer therapy. ..
  36. Yu F, Liao M, Lee J, Shih W. Induction of hepatoma cells migration by phosphoglucose isomerase/autocrine motility factor through the upregulation of matrix metalloproteinase-3. Biochem Biophys Res Commun. 2004;314:76-82 pubmed
    ..MMP-3 inhibition abolished the PGI/AMF-induced cell motility. The observations are consistent with a downstream mediation role of MMP-3 in PGI/AMF-stimulated tumor cell metastasis. ..
  37. Lagana A, Goetz J, Y N, Altschuler Y, Nabi I. pH-specific sequestration of phosphoglucose isomerase/autocrine motility factor by fibronectin and heparan sulphate. J Cell Sci. 2005;118:4175-85 pubmed
    ..The multiple ways of cellular association of PGI/AMF may represent acquired mechanisms to regulate and harness the cytokine function of PGI/AMF. ..
  38. Fairbank M, St Pierre P, Nabi I. The complex biology of autocrine motility factor/phosphoglucose isomerase (AMF/PGI) and its receptor, the gp78/AMFR E3 ubiquitin ligase. Mol Biosyst. 2009;5:793-801 pubmed publisher
    ..Expression of both AMF/PGI and gp78/AMFR is associated with cancer and, in this review, we will discuss various aspects of the biology of this ligand-receptor complex and its role in tumor progression. ..
  39. Funasaka T, Hu H, Hogan V, Raz A. Down-regulation of phosphoglucose isomerase/autocrine motility factor expression sensitizes human fibrosarcoma cells to oxidative stress leading to cellular senescence. J Biol Chem. 2007;282:36362-9 pubmed
  40. Funasaka T, Hogan V, Raz A. Phosphoglucose isomerase/autocrine motility factor mediates epithelial and mesenchymal phenotype conversions in breast cancer. Cancer Res. 2009;69:5349-56 pubmed publisher
    ..These results suggest for the first time that PGI/AMF is a key gene to both EMT in the initiating step of cancer metastasis and MET in the later stage of metastasis during breast cancer progression. ..
  41. Kassahn D, Kolb C, Solomon S, Bochtler P, Illges H. Few human autoimmune sera detect GPI. Nat Immunol. 2002;3:411-2; author reply 412-3 pubmed
  42. Schaller M, Burton D, Ditzel H. Autoantibodies to GPI in rheumatoid arthritis: linkage between an animal model and human disease. Nat Immunol. 2001;2:746-53 pubmed
    ..The results indicate that the immunological events that lead to the development of autoimmune disease in the K/BxN mouse model may also occur in human RA. This data may be used to develop new strategies for therapeutic intervention. ..
  43. Read J, Pearce J, Li X, Muirhead H, Chirgwin J, Davies C. The crystal structure of human phosphoglucose isomerase at 1.6 A resolution: implications for catalytic mechanism, cytokine activity and haemolytic anaemia. J Mol Biol. 2001;309:447-63 pubmed
    ..The human PGI structure has also provided a detailed framework with which to map mutations associated with non-spherocytic haemolytic anaemia. ..
  44. Funasaka T, Yanagawa T, Hogan V, Raz A. Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. FASEB J. 2005;19:1422-30 pubmed
  45. Lee J, Jeffery C. The crystal structure of rabbit phosphoglucose isomerase complexed with D-sorbitol-6-phosphate, an analog of the open chain form of D-glucose-6-phosphate. Protein Sci. 2005;14:727-34 pubmed
    ..The PGI/S6P structure represents the conformation of the enzyme and substrate between the ring opening (or ring closing) step and the isomerization step and helps to complete the model for PGI's catalytic mechanism. ..
  46. Steinke D, Hoegg S, Brinkmann H, Meyer A. Three rounds (1R/2R/3R) of genome duplications and the evolution of the glycolytic pathway in vertebrates. BMC Biol. 2006;4:16 pubmed
    ..The tissue-specific expression might have led to an increased retention for some genes since paralogs can subdivide the ancestral expression domain or find new functions, which are not necessarily related to the original function. ..
  47. Schaller M, Stohl W, Tan S, Benoit V, Hilbert D, Ditzel H. Raised levels of anti-glucose-6-phosphate isomerase IgG in serum and synovial fluid from patients with inflammatory arthritis. Ann Rheum Dis. 2005;64:743-9 pubmed
    ..Anti-GPI Abs may serve a pathogenic function in humans by promoting the maintenance of existing disease. ..
  48. Faik P, Walker J, Redmill A, Morgan M. Mouse glucose-6-phosphate isomerase and neuroleukin have identical 3' sequences. Nature. 1988;332:455-7 pubmed
    ..We report here that there is complete sequence identity between the 759 nucleotides at the 3' end of this clone (coding and non-coding) and the sequence of mouse neuroleukin. ..
  49. Iwanami K, Matsumoto I, Tanaka Y, Inoue A, Goto D, Ito S, et al. Arthritogenic T cell epitope in glucose-6-phosphate isomerase-induced arthritis. Arthritis Res Ther. 2008;10:R130 pubmed publisher
    ..We undertook this study to identify GPI-specific T cell epitopes in DBA/1 mice (H-2q) and investigate the mechanisms of arthritis generation...
  50. Shih W, Liao M, Lin P, Chang C, Cheng H, Yu F, et al. PI 3-kinase/Akt and STAT3 are required for the prevention of TGF-beta-induced Hep3B cell apoptosis by autocrine motility factor/phosphoglucose isomerase. Cancer Lett. 2010;290:223-37 pubmed publisher
    ..We also demonstrated that STAT3 is a weak anti-apoptotic agent but has an increased anti-apoptotic effect in cooperation with PI 3-kinase/Akt. ..
  51. Matsumoto I, Maccioni M, Lee D, Maurice M, Simmons B, Brenner M, et al. How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nat Immunol. 2002;3:360-5 pubmed
    ..This may constitute a generic scenario of arthritogenesis, in which extra-articular proteins coat the cartilage or joint extracellular matrix. ..
  52. Herve C, Wait R, Venables P. Glucose-6-phosphate isomerase is not a specific autoantigen in rheumatoid arthritis. Rheumatology (Oxford). 2003;42:986-8 pubmed
    ..In addition, we showed that another polypeptide identified as phosphoglucomutase was also present in the preparation and reacted with human immunoglobulins. Our findings suggest that GPI is not a specific autoantigen in RA. ..
  53. Kamradt T, Schubert D. The role and clinical implications of G6PI in experimental models of rheumatoid arthritis. Arthritis Res Ther. 2005;7:20-8 pubmed
  54. Matsumoto I, Lee D, Goldbach Mansky R, Sumida T, Hitchon C, Schur P, et al. Low prevalence of antibodies to glucose-6-phosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders. Arthritis Rheum. 2003;48:944-54 pubmed
    ..While the antibody-mediated mechanism at play in the mouse model may exemplify a generic mechanism for some forms of arthritis in humans, GPI itself does not appear to be a target common to the majority of RA patients. ..