Glucose-6-phosphate isomerase explained

Glucose-6-phosphate isomerase
Ec Number:5.3.1.9
Cas Number:9001-41-6
Go Code:0004347
Width:270
Symbol:bact-PGI_C
Bacterial phosphoglucose isomerase C-terminal region
Pfam:PF10432
Cdd:cd05016
Interpro:IPR019490
Symbol:PGI
Phosphoglucose isomeras
Pfam:PF00342
Scop:1pgi
Cdd:cd05015

Glucose-6-phosphate isomerase (GPI), alternatively known as phosphoglucose isomerase/phosphoglucoisomerase (PGI) or phosphohexose isomerase (PHI), is an enzyme that in humans is encoded by the GPI gene on chromosome 19.[1] This gene encodes a member of the glucose phosphate isomerase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In the cytoplasm, the gene product functions as a glycolytic enzyme (glucose-6-phosphate isomerase) that interconverts glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P). Extracellularly, the encoded protein (also referred to as neuroleukin) functions as a neurotrophic factor that promotes survival of skeletal motor neurons and sensory neurons, and as a lymphokine that induces immunoglobulin secretion. The encoded protein is also referred to as autocrine motility factor (AMF) based on an additional function as a tumor-secreted cytokine and angiogenic factor. 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014][2]

Structure

Functional GPI is a 64-kDa dimer composed of two identical monomers.[3] 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.

GPI 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.[4] 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.[5] The large domain, located at the N-terminal, and the C-terminal of each monomer also contain "arm-like" protrusions.[6] Several residues in the small domain serve to bind phosphate, while other residues, particularly His388, from the large and C-terminal domains are crucial to the sugar ring-opening step catalyzed by this enzyme. Since the isomerization activity occurs at the dimer interface, the dimer structure of this enzyme is critical to its catalytic function.[6]

It is hypothesized that serine phosphorylation of this protein induces a conformational change to its secretory form.[3]

Mechanism

The mechanism that GPI uses to interconvert glucose 6-phosphate and fructose 6-phosphate (aldose to ketose) consists of three major steps: opening the glucose ring, isomerizing glucose into fructose through an enediol intermediate, and closing the fructose ring.[7]

Isomerization of glucose

Glucose 6-phosphate binds to GPI in its pyranose form. 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 substrate 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 deprotonating the C5 hydroxyl with Lys518.[8]

When going from fructose-6-phosphate toward glucose-6-phosphate, the result could be mannose-6-phosphate if carbon C2 is given the wrong chirality, but the enzyme does not permit that result except at a very low, non-physiological, rate.[8]

Function

This gene belongs to the GPI family.[2] The protein encoded by this gene is a dimeric enzyme that catalyzes the reversible isomerization of G6P and F6P.[9] [10] Since the reaction is reversible, its direction is determined by G6P and F6P concentrations.[6]

glucose 6-phosphate ↔ fructose 6-phosphate

The protein has different functions inside and outside the cell. In the cytoplasm, the protein is involved in glycolysis and gluconeogenesis, as well as the pentose phosphate pathway.[6] Outside the cell, it functions as a neurotrophic factor for spinal and sensory neurons, called neuroleukin.[10] The same protein is also secreted by cancer cells, where it is called autocrine motility factor[11] and stimulates metastasis.[12] Extracellular GPI is also known to function as a maturation factor.[6] [10]

Neuroleukin

Though originally treated as separate proteins, cloning technology demonstrated that GPI is almost identical to the protein neuroleukin.[13] Neuroleukin is a neurotrophic factor for spinal and sensory neurons. It is found in large amounts in muscle, brain, heart, and kidneys.[14] 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.[15]

Autocrine motility factor

Cloning experiments also revealed that GPI is identical to the protein known as autocrine motility factor (AMF).[16] AMF produced and secreted by cancer cells and stimulates cell growth and motility as a growth factor.[17] AMF is thought to play a key role in cancer metastasis by activating the MAPK/ERK or PI3K/AKT pathways.[18] [19] In the PI3K/AKT pathway, AMF interacts with gp78/AMFR to regulate ER calcium release, and therefore protect against apoptosis in response to ER stress.[20]

Prokaryotic bifunctional glucose-6-phosphate isomerase

In some archaea and bacteria glucose-6-phosphate isomerase activity occurs via a bifunctional enzyme that also exhibits phosphomannose isomerase (PMI) activity. Though not closely related to eukaryotic GPIs, 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 GPI. The enzyme is thought to use the same catalytic mechanisms for both glucose ring-opening and isomerization for the interconversion of G6P to F6P.[21]

Clinical significance

A deficiency of GPI is responsible for 4% of the hemolytic anemias due to glycolytic enzyme deficiencies.[9] [10] [22] [23] Several cases of GPI deficiency have recently been identified.[24]

Elevated serum GPI levels have been used as a prognostic biomarker for colorectal, breast, lung, kidney, gastrointestinal, and other cancers.[3] [10] As AMF, GPI is attributed with regulating cell migration during invasion and metastasis.[3] One study showed that the external layers of breast tumor spheroids (BTS) secrete GPI, which induces epithelial–mesenchymal transition (EMT), invasion, and metastasis in BTS. The GPI inhibitors ERI4P and 6PG were found to block metastasis of BTS but not BTS glycolysis or fibroblast viability. In addition, GPI is secreted exclusively by tumor cells and not normal cells. For these reasons, GPI inhibitors may be a safer, more targeted approach for anti-cancer therapy.[25] GPI also participates in a positive feedback loop with HER2, a major breast cancer therapeutic target, as GPI enhances HER2 expression and HER2 overexpression enhances GPI expression, and so on. As a result, GPI activity likely confers resistance in breast cancer cells against HER2-based therapies using Herceptin/Trastuzumab, and should be considered as an additional target when treating patients.[19]

Applications

Human GPI is capable of inducing arthritis in mice with varied genetic backgrounds via intradermal injection.[26] [27]

See also

Interactions

GPI is known to interact with:

Further reading

External links

Notes and References

  1. Web site: UniProtKB: P06744 (G6PI_HUMAN).
  2. Web site: Entrez Gene: GPI glucose phosphate isomerase.
  3. Haga A, Niinaka Y, Raz A . Phosphohexose isomerase/autocrine motility factor/neuroleukin/maturation factor is a multifunctional phosphoprotein . Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology . 1480 . 1–2 . 235–244 . July 2000 . 11004567 . 10.1016/s0167-4838(00)00075-3 .
  4. Sun YJ, Chou CC, Chen WS, Wu RT, Meng M, Hsiao CD . The crystal structure of a multifunctional protein: phosphoglucose isomerase/autocrine motility factor/neuroleukin . Proceedings of the National Academy of Sciences of the United States of America . 96 . 10 . 5412–5417 . May 1999 . 10318897 . 21873 . 10.1073/pnas.96.10.5412 . free . 1999PNAS...96.5412S .
  5. Jeffery CJ, Bahnson BJ, Chien W, Ringe D, Petsko GA . Crystal structure of rabbit phosphoglucose isomerase, a glycolytic enzyme that moonlights as neuroleukin, autocrine motility factor, and differentiation mediator . Biochemistry . 39 . 5 . 955–964 . February 2000 . 10653639 . 10.1021/bi991604m .
  6. Cordeiro AT, Godoi PH, Silva CH, Garratt RC, Oliva G, Thiemann OH . Crystal structure of human phosphoglucose isomerase and analysis of the initial catalytic steps . Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics . 1645 . 2 . 117–122 . February 2003 . 12573240 . 10.1016/s1570-9639(02)00464-8 .
  7. 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 . Journal of Molecular Biology . 309 . 2 . 447–463 . June 2001 . 11371164 . 10.1006/jmbi.2001.4680 .
  8. Solomons JT, Zimmerly EM, Burns S, Krishnamurthy N, Swan MK, Krings S, Muirhead H, Chirgwin J, Davies C . 6 . 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 . Journal of Molecular Biology . 342 . 3 . 847–860 . September 2004 . 15342241 . 10.1016/j.jmb.2004.07.085 .
  9. Kugler W, Lakomek M . Glucose-6-phosphate isomerase deficiency . Baillière's Best Practice & Research. Clinical Haematology . 13 . 1 . 89–101 . March 2000 . 10916680 . 10.1053/beha.1999.0059 .
  10. Somarowthu S, Brodkin HR, D'Aquino JA, Ringe D, Ondrechen MJ, Beuning PJ . A tale of two isomerases: compact versus extended active sites in ketosteroid isomerase and phosphoglucose isomerase . Biochemistry . 50 . 43 . 9283–9295 . November 2011 . 21970785 . 10.1021/bi201089v .
  11. Dobashi Y, Watanabe H, Sato Y, Hirashima S, Yanagawa T, Matsubara H, Ooi A . Differential expression and pathological significance of autocrine motility factor/glucose-6-phosphate isomerase expression in human lung carcinomas . The Journal of Pathology . 210 . 4 . 431–440 . December 2006 . 17029220 . 10.1002/path.2069 . 39800980 .
  12. Watanabe H, Takehana K, Date M, Shinozaki T, Raz A . Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide . Cancer Research . 56 . 13 . 2960–2963 . July 1996 . 8674049 .
  13. Chaput M, Claes V, Portetelle D, Cludts I, Cravador A, Burny A, Gras H, Tartar A . 6 . The neurotrophic factor neuroleukin is 90% homologous with phosphohexose isomerase . Nature . 332 . 6163 . 454–455 . March 1988 . 3352744 . 10.1038/332454a0 . 4260489 . 1988Natur.332..454C .
  14. Gurney ME, Heinrich SP, Lee MR, Yin HS . Molecular cloning and expression of neuroleukin, a neurotrophic factor for spinal and sensory neurons . Science . 234 . 4776 . 566–574 . October 1986 . 3764429 . 10.1126/science.3764429 . 1986Sci...234..566G .
  15. Gurney ME, Apatoff BR, Spear GT, Baumel MJ, Antel JP, Bania MB, Reder AT . Neuroleukin: a lymphokine product of lectin-stimulated T cells . Science . 234 . 4776 . 574–581 . October 1986 . 3020690 . 10.1126/science.3020690 . 1986Sci...234..574G .
  16. Watanabe H, Takehana K, Date M, Shinozaki T, Raz A . Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide . Cancer Research . 56 . 13 . 2960–2963 . July 1996 . 8674049 .
  17. Silletti S, Raz A . Autocrine motility factor is a growth factor . Biochemical and Biophysical Research Communications . 194 . 1 . 446–457 . July 1993 . 8392842 . 10.1006/bbrc.1993.1840 .
  18. Liotta LA, Mandler R, Murano G, Katz DA, Gordon RK, Chiang PK, Schiffmann E . Tumor cell autocrine motility factor . Proceedings of the National Academy of Sciences of the United States of America . 83 . 10 . 3302–3306 . May 1986 . 3085086 . 323501 . 10.1073/pnas.83.10.3302 . free . 1986PNAS...83.3302L .
  19. Kho DH, Nangia-Makker P, Balan V, Hogan V, Tait L, Wang Y, Raz A . Autocrine motility factor promotes HER2 cleavage and signaling in breast cancer cells . Cancer Research . 73 . 4 . 1411–1419 . February 2013 . 23248119 . 3577983 . 10.1158/0008-5472.can-12-2149 .
  20. Fu M, Li L, Albrecht T, Johnson JD, Kojic LD, Nabi IR . Autocrine motility factor/phosphoglucose isomerase regulates ER stress and cell death through control of ER calcium release . Cell Death and Differentiation . 18 . 6 . 1057–1070 . June 2011 . 21252914 . 3131941 . 10.1038/cdd.2010.181 .
  21. Swan MK, Hansen T, Schönheit P, Davies C . 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 . The Journal of Biological Chemistry . 279 . 38 . 39838–39845 . September 2004 . 15252053 . 10.1074/jbc.M406855200 . free .
  22. Walker JI, Layton DM, Bellingham AJ, Morgan MJ, Faik P . DNA sequence abnormalities in human glucose 6-phosphate isomerase deficiency . Human Molecular Genetics . 2 . 3 . 327–329 . March 1993 . 8499925 . 10.1093/hmg/2.3.327 .
  23. Kanno H, Fujii H, Hirono A, Ishida Y, Ohga S, Fukumoto Y, Matsuzawa K, Ogawa S, Miwa S . 6 . Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia . Blood . 88 . 6 . 2321–2325 . September 1996 . 8822954 . 10.1182/blood.V88.6.2321.bloodjournal8862321 . free .
  24. Web site: GPI Deficiency. 2012-12-23. 2014-05-17. https://web.archive.org/web/20140517142116/http://gpideficiency.org/. dead.
  25. Gallardo-Pérez JC, Rivero-Segura NA, Marín-Hernández A, Moreno-Sánchez R, Rodríguez-Enríquez S . GPI/AMF inhibition blocks the development of the metastatic phenotype of mature multi-cellular tumor spheroids . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1843 . 6 . 1043–1053 . June 2014 . 24440856 . 10.1016/j.bbamcr.2014.01.013 . free .
  26. Pizzolla A, Wing K, Holmdahl R . A glucose-6-phosphate isomerase peptide induces T and B cell-dependent chronic arthritis in C57BL/10 mice: arthritis without reactive oxygen species and complement . The American Journal of Pathology . 183 . 4 . 1144–1155 . October 2013 . 23911657 . 10.1016/j.ajpath.2013.06.019 . free .
  27. Inoue A, Matsumoto I, Tanaka Y, Iwanami K, Kanamori A, Ochiai N, Goto D, Ito S, Sumida T . 6 . Tumor necrosis factor alpha-induced adipose-related protein expression in experimental arthritis and in rheumatoid arthritis . Arthritis Research & Therapy . 11 . 4 . R118 . 2009 . 19660107 . 10.1186/ar2779 . 2745801 . free .

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