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UDP-GlcNAc 2-Epimerase/ManNAc Kinase (GNE)

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Handbook of Glycosyltransferases and Related Genes

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Abstract

N-Acetylneuraminic acid (Neu5Ac) or sialic acid is a pivotal structural and functional monosaccharide in any mammalian cell surface. In the membrane bound or soluble glycoconjugates, this electronegatively charged sugar is localized in the terminal position. Neu5Ac mediates recognition processes like cell-cell, cell-matrix, receptor-mediator, or cell-pathogen interactions (Varki 1997; Schauer 2004). Neu5Ac is formed in vivo by a multistep pathway (Roseman 1970) beginning with the conversion of fructose-6-P to glucosamine-6-P, which is further metabolized to UDP-N-acetylglucosamine (UDP-GlcNAc), the crucial precursor of Neu5Ac, by the hexosamine pathway. This substrate is converted to N-acetylmannosamine (ManNAc) by a specific UDP-GlcNAc 2-epimerase and then phosphorylated to ManNAc 6-P (Fig. 134.1). Both reactions are catalyzed by one enzyme, the bifunctional UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE). ManNAc 6-P is then condensed with phosphoenolpyruvate forming sialic acid 9-P. This compound is further metabolized to CMP-sialic acid, which is transported to the Golgi apparatus, and they are used for the formation of sialylated glycoconjugates (Fig. 134.1).

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References

  • Al-Rawi S, Hinderlich S, Reutter W, Giannis A (2004) Synthesis and biochemical properties of reversible inhibitors of UDP-N-acetylglucosamine 2-epimerase. Angew Chem Int Ed Engl 43:4366–4370

    Article  CAS  PubMed  Google Scholar 

  • Amsili S, Zer H, Hinderlich S, Krause S, Becker-Cohen M, MacArthur DG, North KN, Mitrani-Rosenbaum S (2008) UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) binds to alpha-actinin 1: novel pathways in skeletal muscle? PLoS One 3:e2477

    Article  PubMed Central  PubMed  Google Scholar 

  • Argov Z, Mitrani-Rosenbaum S (2008) The hereditary inclusion body myopathy enigma and its future therapy. Neurotherapeutics 5:633–637

    Article  CAS  PubMed  Google Scholar 

  • Benie AJ, Blume A, Schmidt RR, Reutter W, Hinderlich S, Peters T (2004) Characterization of ligand binding to the bifunctional key enzyme in the sialic acid biosynthesis by NMR: II. Investigation of the ManNAc kinase functionality. J Biol Chem 279:55722–55727

    Article  CAS  PubMed  Google Scholar 

  • Blume A, Benie AJ, Stolz F, Schmidt RR, Reutter W, Hinderlich S, Peters T (2004a) Characterization of ligand binding to the bifunctional key enzyme in the sialic acid biosynthesis by NMR: I. Investigation of the UDP-GlcNAc 2-epimerase functionality. J Biol Chem 279:55715–55721

    Article  CAS  PubMed  Google Scholar 

  • Blume A, Ghaderi D, Liebich V, Hinderlich S, Donner P, Reutter W, Lucka L (2004b) UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, functionally expressed in and purified from Escherichia coli, yeast, and insect cells. Protein Expr Purif 35:387–396

    Article  CAS  PubMed  Google Scholar 

  • Cardini CE, Leloir LF (1957) Enzymatic formation of acetylgalactosamine. J Biol Chem 225:317–324

    CAS  PubMed  Google Scholar 

  • Comb DG, Roseman S (1958) Enzymatic synthesis of N-acetyl-D-mannosamine. Biochim Biophys Acta 29:653–654

    Article  CAS  PubMed  Google Scholar 

  • Effertz K, Hinderlich S, Reutter W (1999) Selective loss of either the epimerase or kinase activity of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase due to site-directed mutagenesis based on sequence alignments. J Biol Chem 274:28771–28778

    Article  CAS  PubMed  Google Scholar 

  • Eisenberg I, Avidan N, Potikha T, Hochner H, Chen M, Olender T, Barash M, Shemesh M, Sadeh M, Grabov-Nardini G, Shmilevich I, Friedmann A, Karpati G, Bradley WG, Baumbach L, Lancet D, Asher EB, Beckmann JS, Argov Z, Mitrani-Rosenbaum S (2001) The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 29:83–87

    Article  CAS  PubMed  Google Scholar 

  • Fontaine G, Biserte G, Montreuil J, Dupont A, Farriaux JP (1968) Sialuria: an original metabolic disorder. Helv Paediatr Acta 17:1–32

    Google Scholar 

  • Galeano B, Klootwijk R, Manoli I, Sun M, Ciccone C, Darvish D, Starost MF, Zerfas PM, Hoffmann VJ, Hoogstraten-Miller S, Krasnewich DM, Gahl WA, Huizing M (2007) Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. J Clin Invest 117:1585–1594

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ghaderi D, Strauss HM, Reinke S, Cirak S, Reutter W, Lucka L, Hinderlich S (2007) Evidence for dynamic interplay of different oligomeric states of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase by biophysical methods. J Mol Biol 369:746–758

    Article  CAS  PubMed  Google Scholar 

  • Giordanengo V, Ollier L, Lanteri M, Lesimple J, March D, Thyss S, Lefebvre JC (2004) Epigenetic reprogramming of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) in HIV-1-infected CEM T cells. FASEB J 18:1961–1963

    CAS  PubMed  Google Scholar 

  • Gosh S, Roseman S (1961) Enzymatic phosphorylation of N-acetyl-D-mannosamine. Proc Natl Acad Sci U S A 47:955–958

    Article  Google Scholar 

  • Harms E, Kreisel W, Morris HP, Reutter W (1973) Biosynthesis of N-acetylneuraminic acid in Morris hepatomas. Eur J Biochem 32:254–262

    Article  CAS  PubMed  Google Scholar 

  • Hinderlich S, Stäsche R, Zeitler R, Reutter W (1997) A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. Purification and characterization of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. J Biol Chem 272:24313–24318

    Article  CAS  PubMed  Google Scholar 

  • Horstkorte R, Nöhring S, Danker K, Effertz K, Reutter W, Lucka L (2000) Protein kinase C phosphorylates and regulates UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase. FEBS Lett 470:315–318

    Article  CAS  PubMed  Google Scholar 

  • Huizing M, Krasnewich DM (2009) Hereditary inclusion body myopathy: a decade of progress. Biochim Biophys Acta 1792:881–887

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ito M, Sugihara K, Asaka T, Toyama T, Yoshihara T, Furuichi K, Wada T, Asano M (2012) Glycoprotein hyposialylation gives rise to a nephrotic-like syndrome that is prevented by sialic acid administration in GNE V572L point-mutant mice. PLoS One 7:e29873

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kakani S, Yardeni T, Poling J, Ciccone C, Niethamer T, Klootwijk ED, Manoli I, Darvish D, Hoogstraten-Miller S, Zerfas P, Tian E, Ten Hagen KG, Kopp JB, Gahl WA, Huizing M (2012) The Gne M712T mouse as a model for human glomerulopathy. Am J Pathol 180:1431–1440

    Article  CAS  PubMed  Google Scholar 

  • Kayser H, Zeitler R, Kannicht C, Grunow D, Nuck R, Reutter W (1992) Biosynthesis of a nonphysiological sialic acid in different rat organs, using N-propanoyl-D-hexosamines as precursors. J Biol Chem 267:16934–16938

    CAS  PubMed  Google Scholar 

  • Kemmner W, Kessel P, Sanchez-Ruderisch H, Möller H, Hinderlich S, Schlag PM, Detjen K (2012) Loss of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) induces apoptotic processes in pancreatic carcinoma cells. FASEB J 26:938–946

    Article  CAS  PubMed  Google Scholar 

  • Keppler OT, Hinderlich S, Langner J, Schwartz-Albiez R, Reutter W, Pawlita M (1999) UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation. Science 284:1372–1376

    Article  CAS  PubMed  Google Scholar 

  • Kikuchi K, Tsuiki S (1973) Purification and properties of UDP-N-acetylglucosamine 2′-epimerase from rat liver. Biochim Biophys Acta 327:193–206

    Article  CAS  PubMed  Google Scholar 

  • Kornfeld S, Kornfeld R, Neufeld E, O’Brien PJ (1964) The feedback control of sugar nucleotide biosynthesis in liver. Proc Natl Acad Sci U S A 52:371–379

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kundig W, Gosh S, Roseman S (1966) The sialic acids. VII. N-Acyl-D-mannosamine kinase from rat liver. J Biol Chem 241:5619–5626

    CAS  PubMed  Google Scholar 

  • Malicdan MC, Noguchi S, Nonaka I, Hayashi YK, Nishino I (2007) A Gne knockout mouse expressing human GNE D176V mutation develops features similar to distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy. Hum Mol Genet 16:2669–2682

    Article  CAS  PubMed  Google Scholar 

  • Malicdan MC, Noguchi S, Tokutomi T, Goto Y, Nonaka I, Hayashi YK, Nishino I (2012) Peracetylated N-acetylmannosamine, a synthetic sugar molecule, efficiently rescues muscle phenotype and biochemical defects in mouse model of sialic acid-deficient myopathy. J Biol Chem 287:2689–2705

    Article  CAS  PubMed  Google Scholar 

  • Martinez J, Nguyen LD, Hinderlich S, Zimmer R, Tauberger E, Reutter W, Saenger W, Fan H, Moniot S (2012) Crystal structures of N-acetylmannosamine kinase provide insights into enzyme activity and inhibition. J Biol Chem 287:13656–13665

    Article  CAS  PubMed  Google Scholar 

  • Möller H, Böhrsch V, Lucka L, Hackenberger CP, Hinderlich S (2011) Efficient metabolic oligosaccharide engineering of glycoproteins by UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) knock-down. Mol Biosyst 7:2245–2251

    Article  PubMed  Google Scholar 

  • Montreuil J, Biserte G, Strecker G, Spik G, Fontaine G, Farriaux JP (1968) Description of a new type of melituria, called sialuria. Clin Chim Acta 21:61–69

    Article  CAS  PubMed  Google Scholar 

  • Nemunaitis G, Jay CM, Maples PB, Gahl WA, Huizing M, Yardeni T, Tong AW, Phadke AP, Pappen BO, Bedell C, Allen H, Hernandez C, Templeton NS, Kuhn J, Senzer N, Nemunaitis J (2011) Hereditary inclusion body myopathy: single patient response to intravenous dosing of GNE gene lipoplex. Hum Gene Ther 22:1331–1341

    Article  CAS  PubMed  Google Scholar 

  • Niethamer TK, Yardeni T, Leoyklang P, Ciccone C, Astiz-Martinez A, Jacobs K, Dorward HM, Zerfas PM, Gahl WA, Huizing M (2012) Oral monosaccharide therapies to reverse renal and muscle hyposialylation in a mouse model of GNE myopathy. Mol Genet Metab 107:748–755

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nishino I, Noguchi S (2012) Sialic acid supplementation therapy for distal myopathy with rimmed vacuoles (GNE myopathy). Rinsho Shinkeigaku 52:1210–1212

    Article  PubMed  Google Scholar 

  • Nishino I, Noguchi S, Murayama K, Driss A, Sugie K, Oya Y, Nagata T, Chida K, Takahashi T, Takusa Y, Ohi T, Nishimiya J, Sunohara N, Ciafaloni E, Kawai M, Aoki M, Nonaka I (2002) Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 59:1689–1693

    Article  CAS  PubMed  Google Scholar 

  • Oetke C, Hinderlich S, Reutter W, Pawlita M (2003) Epigenetically mediated loss of UDP-GlcNAc 2-epimerase/ManNAc kinase expression in hyposialylated cell lines. Biochem Biophys Res Commun 308:892–898

    Article  CAS  PubMed  Google Scholar 

  • Reinke SO, Hinderlich S (2007) Prediction of three different isoforms of the human UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. FEBS Lett 581:3327–3331

    Article  CAS  PubMed  Google Scholar 

  • Reinke SO, Lehmer G, Hinderlich S, Reutter W (2009) Regulation and pathophysiological implications of UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) as the key enzyme of sialic acid biosynthesis. Biol Chem 390:591–599

    Article  CAS  PubMed  Google Scholar 

  • Roseman S (1970) The synthesis of complex carbohydrates by multiglycosyltransferase systems and their potential function in intercellular adhesion. Chem Phys Lipids 5:270–297

    Article  CAS  PubMed  Google Scholar 

  • Salo WL, Fletcher HG (1970) Studies on the mechanism of action of uridine diphosphate N-acetylglucosamine 2-epimerase. Biochemistry 9:878–881

    Article  CAS  PubMed  Google Scholar 

  • Saxon E, Bertozzi CR (2000) Cell surface engineering by a modified Staudinger reaction. Science 287:2007–2010

    Article  CAS  PubMed  Google Scholar 

  • Schauer R (2004) Sialic acids: fascinating sugars in higher animals and man. Zoology 107:49–64

    Article  CAS  PubMed  Google Scholar 

  • Schwarzkopf M, Knobeloch KP, Rohde E, Hinderlich S, Wiechens N, Lucka L, Horak I, Reutter W, Horstkorte R (2002) Sialylation is essential for early development in mice. Proc Natl Acad Sci U S A 99:5267–5270

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Seppala R, Lehto VP, Gahl WA (1999) Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme. Am J Hum Genet 64:1563–1569

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sommar KM, Ellis DB (1972) Uridine diphosphate N-acetyl-D-glucosamine 2-epimerase from rat liver. I. Catalytic and regulatory properties. Biochim Biophys Acta 268:581–589

    Article  CAS  PubMed  Google Scholar 

  • Spivak CT, Roseman S (1966) UDP-N-acetyl-D-glucosamine 2′-epimerase. Methods Enzymol 9:612–615

    Article  CAS  Google Scholar 

  • Stäsche R, Hinderlich S, Weise C, Effertz K, Lucka L, Moormann P, Reutter W (1997) A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. Molecular cloning and functional expression of UDP-N-acetyl-glucosamine 2-epimerase/N-acetylmannosamine kinase. J Biol Chem 272:24319–24324

    Article  PubMed  Google Scholar 

  • Stolz F, Reiner M, Blume A, Reutter W, Schmidt RR (2004) Novel UDP-glycal derivatives as transition state analogue inhibitors of UDP-GlcNAc 2-epimerase. J Org Chem 69:665–679

    Article  CAS  PubMed  Google Scholar 

  • Tong Y, Tempel W, Nedyalkova L, Mackenzie F, Park HW (2009) Crystal structure of the N-acetylmannosamine kinase domain of GNE. PLoS One 4:e7165

    Article  PubMed Central  PubMed  Google Scholar 

  • Varki A (1997) Sialic acids as ligands in recognition phenomena. FASEB J 11:248–255

    CAS  PubMed  Google Scholar 

  • Weidemann W, Stelzl U, Lisewski U, Bork K, Wanker EE, Hinderlich S, Horstkorte R (2006) The collapsin response mediator protein 1 (CRMP-1) and the promyelocytic leukemia zinc finger protein (PLZF) bind to UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme of sialic acid biosynthesis. FEBS Lett 580:6649–6654

    Article  CAS  PubMed  Google Scholar 

  • Weiss P, Tietze F, Gahl WA, Seppala R, Ashwell G (1989) Identification of the metabolic defect in sialuria. J Biol Chem 264:17635–17636

    CAS  PubMed  Google Scholar 

  • Yardeni T, Choekyi T, Jacobs K, Ciccone C, Patzel K, Anikster Y, Gahl WA, Kurochkina N, Huizing M (2011) Identification, tissue distribution, and molecular modeling of novel human isoforms of the key enzyme in sialic acid synthesis, UDP-GlcNAc 2-epimerase/ManNAc kinase. Biochemistry 50:8914–8925

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute of Biochemistry and Molecular Biology, Charité - Universitätsmedizin Berlin, Arnimallee 22, 14195, Berlin-Dahlem, Germany

    Prof. Werner Reutter

  2. Department of Life Sciences and Technology, Beuth Hochschule für Technik Berlin - University of Applied Sciences, Seestr. 64, 13347, Berlin, Germany

    Prof. Stephan Hinderlich

  3. Charite - Universitätsmedizin Berlin, Experimental and Clinical Research Center, Berlin, Germany

    Dr. Wolfgang Kemmner

Authors
  1. Prof. Werner Reutter
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  2. Prof. Stephan Hinderlich
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  3. Dr. Wolfgang Kemmner
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Corresponding author

Correspondence to Werner Reutter .

Editor information

Editors and Affiliations

  1. RIKEN-Max-Planck Joint Research Center for Systems Chemical Biology, RIKEN, Wako, Saitama, Japan

    Naoyuki Taniguchi

  2. Department of Biochemistry, Kochi University, Medical School, Nankoku, Kochi, Japan

    Koichi Honke

  3. Sanford Burnham Medical Research Institute, La Jolla, California, USA

    Minoru Fukuda

  4. Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan

    Hisashi Narimatsu

  5. RIKEN-Max-Planck Joint Research Center for Systems Chemical Biology, RIKEN, Wako, Saitama, Japan

    Yoshiki Yamaguchi

  6. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

    Takashi Angata

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Reutter, W., Hinderlich, S., Kemmner, W. (2014). UDP-GlcNAc 2-Epimerase/ManNAc Kinase (GNE). In: Taniguchi, N., Honke, K., Fukuda, M., Narimatsu, H., Yamaguchi, Y., Angata, T. (eds) Handbook of Glycosyltransferases and Related Genes. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54240-7_114

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