Glucose-6-phosphate isomerase

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Glucose-6-phosphate isomerase
Glucose-6-phosphate isomerase
Surface model of the G6PI dimer, on the right a subunit as a cartoon, according to PDB  1JIQ

Existing structural data : 1IAT , 1IRI , 1JIQ , 1JLH , 1NUH

Properties of human protein
Mass / length primary structure 557 amino acids
Secondary to quaternary structure Homodimer
Identifier
Gene name GPI
External IDs
Enzyme classification
EC, category 5.3.1.9 ,  isomerase
Response type Rearrangement
Substrate D -glucose-6-phosphate; D- fructose-6-phosphate
Products D- fructose-6-phosphate; D -glucose-6-phosphate
Occurrence
Homology family CLU_017947_3_0
Parent taxon Creature
Orthologue
human House mouse
Entrez 2821 14751
Ensemble ENSG00000282019 ENSMUSG00000036427
UniProt P06744 P06745
Refseq (mRNA) NM_000175 NM_008155
Refseq (protein) NP_000166 NP_032181
Gene locus Chr 19: 34.36 - 34.4 Mb Chr 7: 34.2 - 34.23 Mb
PubMed search 2821 14751

Glucose-6-phosphate isomerase (GPI) (also phosphohexose isomerase or phosphoglucose isomerase , PGI) is the one enzyme of glycolysis , the conversion of glucose-6-phosphate (G6P) in fructose-phosphate 6 (F6P) catalyzes . This reaction is essential for all living things in order to utilize the energy in carbohydrates. In addition, the reaction is reversible, and the reverse reaction is required for gluconeogenesis . Mutations at GPI - gene , which on chromosome 19 is coded, can cause GPI deficiency, and this is responsible for hemolytic anemia or be more severe disorders already in the newborn. According to new studies, GPI is a factor in the development of arthritis and tumors . The GPI is not identical to the D -Xylose isomerase from the breakdown of starch.

structure

Functional GPI is a dimer with a molecular mass of 64  kDa , which consists of two identical monomers. The two monomers interact in particular through the two protrusions in a close anchoring. The active center of each monomer is formed by a gap between the two domains and the dimer interface.

GPI monomers are made up of two domains, one of which consists of two separate segments called the large domain and the other domain consists of the segment in between, the small domain . The two domains are each αβα sandwiches, with the small domain containing a five-stranded β-sheet surrounded by α-helices , while the large domain contains a six- stranded β-sheet . The large domain located at the N -terminus and C -terminus of each monomer also contains “arm-like” protrusions.

Several residues in the small domain serve to bind phosphate , while other residues, especially His388 , from the large and the C -terminal domains are crucial for 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 crucial for its catalytic function.

It is believed that serine phosphorylation of this protein causes a conformational change in its secretory form.

properties

The protein has different functions inside and outside the cell. In the cytoplasm , the protein is involved in glycolysis, gluconeogenesis and the pentose phosphate pathway . Outside the cell, it acts as a neurotrophic factor for spinal and sensory neurons, called neuroleukin . The same protein is also secreted by cancer cells, where it is called autocrine motility factor (AMF) and stimulates metastasis . It is also known that extracellular GPI acts as a maturation factor. After it has been proven that GPI is identical to the autocrine motility factor and to Neuroleukin, further functions of the GPI protein can be named.

As a neurotrophic factor, it favors the growth and differentiation of spinal and sensory neurons. It is found in large quantities in the muscles, brain, heart, and kidneys. Neuroleukin also acts as a lymphokine , which is secreted by lectin- stimulated T cells . It induces the secretion of immunoglobulin in B cells as part of a response that activates antibody-secreting cells.

As an AMF, it activates the AMF receptor (AMFR). An increased number of these receptors was found on advanced tumor cells. AMF is produced and secreted by cancer cells , and stimulates cell growth and motility as a growth factor. AMF is believed to play a key role in cancer metastasis by activating the MAPK / ERK or PI3K / AKT signaling pathways. In the PI3K / AKT signaling pathway, AMF interacts with the gp78 / AMFR complex to regulate calcium release in the endoplasmic reticulum (ER) and therefore protects against apoptosis in response to ER stress. Activation of the AMFR affects cellular adhesion , motility , sprouting and apoptosis.

In some archaea and bacteria , glucose-6-phosphate isomerase activity occurs via a bifunctional enzyme that also has mannose-6-phosphate isomerase (PMI) activity. Although not closely related to eukaryotic GPI, the bifunctional enzyme is similar enough that the sequence contains the cluster of threonine and serine residues that form the sugar phosphate binding site in conventional GPI. The enzyme is believed to use the same catalytic mechanisms for glucose ring opening and isomerization for the conversion of glucose-6-phosphate to fructose-6-phosphate.

mechanism

The GPI mechanism for converting glucose-6-phosphate (aldose) to fructose-6-phosphate (ketose) consists of three main steps: opening the glucose ring, isomerization of glucose to fructose via an enediolate intermediate and closing the fructose Rings.

Structural formula of α-D-glucose-6-phosphate ⇔ Structural formula of β-D-fructose-6-phosphate
Glucose-6-phosphate is rearranged to fructose-6-phosphate and vice versa.

Glucose-6-phosphate binds to GPI in its pyranose form ( 1 ). The ring is opened by a push-pull mechanism of His388, which protonates the C5 oxygen, and Lys518 , which deprotonates the C1 hydroxyl group , which is why this step is also known as acid-catalyzed ring opening ( 2 ). This creates an open aldose . Then the substrate is rotated about the C3-C4 bond to position it for isomerization. At this moment Glu357 deprotonates the C2 atom to form a cis -endiolate intermediate stabilized by Arg272 (base catalysis, 3 ). To complete the isomerization, Glu357 donates its proton, which was previously exchanged with a proton in the surrounding solution, to the C1 atom, the C2 hydroxyl group loses its proton and the open-chain fructose-6-phosphate is formed (acid catalysis, 4 ). Finally, the ring is closed by rotating the substrate again around the C3-C4 bond and deprotonating the C5 hydroxy group by His388, which is why this step is also known as base-catalyzed ring closure ( 5 ). The product formed (fructose-6-phosphate in its pyranose form) then leaves the active center of glucose-6-phosphate isomerase ( 6 ).

Reaction mechanism of glucose-6-phosphate isomerase
Active center of the glucose-6-phosphate isomerase of the house mouse , according to PDB  1U0F . The substrate glucose-6-phosphate (G6P) is in ring and open-chain form.

pathology

In addition to the hereditary metabolic disorders resulting from a GPI deficiency, a form of arthritis is known which is caused by autoimmunity to GPI. It is now known that IL-6 and T H 17 play a role in the acquisition of this disease.

Elevated serum GPI values have been used as a prognostic biomarker for colon, breast, lung, kidney, stomach, intestinal and other cancers. As AMF, GPI is assigned to regulate cell migration during invasion and metastasis. One study showed that the outer layers of breast tumor spheroids (BTS) secrete GPI, inducing epithelial-mesenchymal transition (EMT), invasion, and metastasis in BTS. The GPI inhibitors ERI4P and 6PG were found to block BTS metastasis, but not BTS glycolysis or fibroblast viability . In addition, GPI is only secreted by tumor cells and not by normal cells. For these reasons, GPI inhibitors could be a safer and more targeted approach to cancer therapy.

GPI also participates in a positive feedback loop with HER2 , a major target for breast cancer, as GPI increases HER2 expression and HER2 overexpression increases GPI expression, and so on. As a result, GPI activity is likely to make breast cancer cells resistant to HER2-based therapies with trastuzumab ( trade name : Herceptin ® ) and should be viewed as an additional target in the treatment of patients.

Web links

Wikibooks: Biochemistry and Pathobiochemistry: Glucose-6-Phosphate Isomerase  - Learning and Teaching Materials

Individual evidence

  1. ↑ UniProt P06744
  2. ^ A b c C.J. Jeffery, BJ Bahnson, W. Chien, D. Rings, GA Petsko: Crystal structure of rabbit phosphoglucose isomerase, a glycolytic enzyme that moonlights as neuroleukin, autocrine motility factor, and differentiation mediator. In: Biochemistry. Volume 39, Number 5, February 2000, pp. 955-964, doi : 10.1021 / bi991604m , PMID 10653639 .
  3. ↑ a b c d A. Haga, Y. Niinaka, A. Raz: Phosphohexose isomerase / autocrine motility factor / neuroleukin / maturation factor is a multifunctional phosphoprotein. In: Biochimica et Biophysica Acta . Volume 1480, Number 1-2, July 2000, pp 235-244, doi : 10.1016 / s0167-4838 (00) 00075-3 , PMID 11004567 .
  4. ↑ YJ Sun, CC Chou, WS Chen, RT Wu, M. Meng, CD Hsiao: The crystal structure of a multifunctional protein: phosphoglucose isomerase / autocrine motility factor / neuroleukin. In: Proceedings of the National Academy of Sciences . Volume 96, number 10, May 1999, pp. 5412-5417, doi : 10.1073 / pnas.96.10.5412 , PMID 10318897 , PMC 21873 (free full text).
  5. ↑ a b c d A. T. Cordeiro, PH Godoi, CH Silva, RC Garratt, G. Oliva, OH Thiemann: Crystal structure of human phosphoglucose isomerase and analysis of the initial catalytic steps. In: Biochimica et Biophysica Acta . Volume 1645, Number 2, February 2003, pp. 117-122, doi : 10.1016 / s1570-9639 (02) 00464-8 , PMID 12573240 .
  6. ↑ a b c S. Somarowthu, HR Brodkin, JA D'Aquino, D. Rings, MJ Ondrechen, PJ Beuning: A tale of two isomerases: compact versus extended active sites in ketosteroid isomerase and phosphoglucose isomerase. In: Biochemistry. Volume 50, Number 43, November 2011, pp. 9283-9295, doi : 10.1021 / bi201089v , PMID 21970785 .
  7. ↑ Y. Dobashi, H. Watanabe, Y. Sato, S. Hirashima, T. Yanagawa, H. Matsubara, A. Ooi: Differential expression and pathological significance of autocrine motility factor / glucose-6-phosphate isomerase expression in human lung carcinomas . In: The Journal of pathology. Volume 210, Number 4, December 2006, pp. 431-440, doi : 10.1002 / path.2069 , PMID 17029220 .
  8. ↑ H. Watanabe, K. Takehana, M. Date, T. Shinozaki, A. Raz: Tumor cell autocrine motility factor is the neuroleukin / phosphohexose isomerase polypeptide. In: Cancer Research . Volume 56, Number 13, July 1996, pp. 2960-2963, PMID 8674049 .
  9. ↑ Glucose-6-phosphate isomerase.  In: Online Mendelian Inheritance in Man . (English).
  10. ↑ ME Gurney, SP Heinrich, MR Lee, HS Yin: Molecular cloning and expression of neuroleukin, a neurotrophic factor for spinal and sensory neurons. In: Science . Volume 234, Number 4776, October 1986, pp. 566-574, doi : 10.1126 / science.3764429 , PMID 3764429 .
  11. Jump up ↑ ME Gurney, BR Apatoff, GT Spear, MJ Baumel, JP Antel, MB Bania, AT Reder: Neuroleukin: a lymphokine product of lectin-stimulated T cells. In: Science . Volume 234, Number 4776, October 1986, pp. 574-581, doi : 10.1126 / science.3020690 , PMID 3020690 .
  12. ↑ S. Silletti, A. Raz: Autocrine motility factor is a growth factor. In: Biochemical and biophysical research communications. Volume 194, Number 1, July 1993, pp. 446-457, doi : 10.1006 / bbrc.1993.1840 , PMID 8392842 .
  13. ↑ a b M. Fu, L. Li, T. Albrecht, JD Johnson, LD Kojic, IR Nabi: Autocrine motility factor / phosphoglucose isomerase regulates ER stress and cell death through control of ER calcium release. In: Cell death and differentiation. Volume 18, number 6, June 2011, pp. 1057-1070, doi : 10.1038 / cdd.2010.181 , PMID 21252914 , PMC 3131941 (free full text).
  14. ↑ LA Liotta, R. Mandler, G. Murano, DA Katz, RK Gordon, PK Chiang, E. Schiffmann: Tumor cell autocrine motility factor. In: Proceedings of the National Academy of Sciences . Volume 83, Number 10, May 1986, pp. 3302-3306, doi : 10.1073 / pnas.83.10.3302 , PMID 3085086 , PMC 323501 (free full text).
  15. ↑ CG Chiu, P. St-Pierre, IR Nabi, SM Wiseman: Autocrine motility factor receptor: a clinical review. In: Expert review of anticancer therapy. Volume 8, Number 2, February 2008, pp. 207-217, doi : 10.1586 / 14737140.8.2.207 , PMID 18279062 (review).
  16. ↑ MK Swan, T. Hansen, P. Schönheit, C. Davies: 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. In: Journal of Biological Chemistry . Volume 279, Number 38, September 2004, pp. 39838-39845, doi : 10.1074 / jbc.M406855200 , PMID 15252053 .
  17. ↑ J. Read, J. Pearce, X. Li, H. Muirhead, J. Chirgwin, C. Davies: The crystal structure of human phosphoglucose isomerase at 1.6 A resolution: implications for catalytic mechanism, cytokine activity and haemolytic anemia. In: Journal of molecular biology. Volume 309, Number 2, June 2001, pp. 447-463, doi : 10.1006 / jmbi.2001.4680 , PMID 11371164 .
  18. ^ Donald Voet, Judith G. Voet, Charlotte W. Pratt: Fundamentals of Biochemistry . Life at the Molecular Level. 5th edition. John Wiley & Sons , Hoboken, NJ 2016, ISBN 978-1-118-91840-1 , pp. 484 ( limited preview in Google Book search).
  19. ↑ a b J. T. Solomons, EM Zimmerly, S. Burns, N. Krishnamurthy, MK Swan, S. Krings, H. Muirhead, J. Chirgwin, C. Davies: 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. In: Journal of molecular biology. Volume 342, number 3, September 2004, pp. 847-860, doi : 10.1016 / j.jmb.2004.07.085 , PMID 15342241 .
  20. ↑ K. Iwanami, I. Matsumoto, Y. Tanaka-Watanabe, A. Inoue, M. Mihara, Y. Ohsugi, M. Mamura, D. Goto, S. Ito, A. Tsutsumi, T. Kishimoto, T. Sumida : Crucial role of the interleukin-6 / interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase. In: Arthritis and rheumatism. Volume 58, Number 3, March 2008, pp. 754-763, doi : 10.1002 / art.23222 , PMID 18311788 .
  21. ^ JC Gallardo-Pérez, NA Rivero-Segura, A. Marín-Hernández, R. Moreno-Sánchez, S. Rodríguez-Enríquez: GPI / AMF inhibition blocks the development of the metastatic phenotype of mature multi-cellular tumor spheroids. In: Biochimica et Biophysica Acta . Volume 1843, number 6, June 2014, pp. 1043-1053, doi : 10.1016 / j.bbamcr.2014.01.013 , PMID 24440856 .
  22. ↑ DH Kho, P. Nangia-Makker, V. Balan, V. Hogan, L. Tait, Y. Wang, A. Raz: Autocrine motility factor promotes HER2 cleavage and signaling in breast cancer cells. In: Cancer Research . Volume 73, number 4, February 2013, pp. 1411-1419, doi : 10.1158 / 0008-5472.CAN-12-2149 , PMID 23248119 , PMC 3577983 (free full text).