Glycosylation and Disease

Jonathan Rhodes, University of Liverpool, Liverpool, UK
Barry J Campbell, University of Liverpool, Liverpool, UK
Lu‐Gang Yu, University of Liverpool, Liverpool, UK

Published online: September 2010

DOI: 10.1002/9780470015902.a0002151.pub2

Glycosylation is the process of attachment of sugar molecules, usually in chains (oligosaccharides), to proteins and lipids to form the glycoproteins and glycolipids found in eukaryotic and some prokaryotic organisms. The presence of oligosaccharides on a protein can have substantial effects on its size, stability, charge and antigenicity. The varying structure, branching and substitution of the carbohydrates in an oligosaccharide results in much greater diversity than would be achieved for a peptide with an equivalent number of residues. Acquired alterations in glycosylation occur in cancer and inflammation and may have particularly important functional consequences when they affect mucosae. They also have the potential to affect pathogen–host and other cell–cell interactions. Congenital glycosylation disorders most commonly affect N-glycosylation and affect development in diverse ways. There is increasing evidence of the importance of interactions between carbohydrate structures and carbohydrate-binding proteins (lectins) which may be extrinsic (dietary or microbial) or intrinsic (mammalian galectins or siglecs).

Key Concepts:

  • Glycosylation occurs as N- and O-linked (mucin type) oligosaccharides (glycans) on glycoproteins and as glycolipids.
  • Variation in sequence, linkage and substitution of carbohdrates in a glycan means that a relatively short glycan can have many more variations (glycoforms) than a peptide with an equivalent number of amino acids.
  • Variations in glycan structure can result from a range of different mechanisms that include altered glycosyltransferase and glycosidase activity, Golgi acidification and structure, donor and acceptor availability.
  • Cell–cell and cell–microbe interactions are often driven by interactions between lectins on one cell and the relevant carbohydrate (glycan) receptor on the other cell.
  • Mucins are heavily glycosylated, particularly with O-linked glycans and this gives them their protective properties.
  • Mammalian lectins include a family of galactose-binding lectins called galectins that interact with some of the glycans that show increased expression in epithelial cancers with increased cancer cell to endothelial adherence and increased metastasis as a consequence.
  • Foodstuffs, particularly legumes, contain lectins some of which resist digestion and may have biologically significant interactions with the intestinal epithelium.
  • A wide range of rare congenital dosorders of glycosylation have been recognised – these have many and varied developmental consequences.
  • Some of the developmental glycosylation disorders can be screened for by isoelectric focusing of serum glycoproteins.

Keywords: glycobiology; glycoproteins; glycolipids; mucins; blood groups; glycocalyx; cell–cell interaction; epithelial–microbe interaction

Figure 1. Major type of asparagine-linked (N linked) saccharide structure in glycoproteins. Asn, asparagine; GlcNAc, N-acetyl-d-glucosamine; Man, mannose and Fuc, fucose.
Figure 2. Possible pathways of O-glycosylation. Fuc, fucose; Gal, d-galactose; GalNAc, N-acetyl-d-galactosamine; GlcNAc, N-acetyl-d-glucosamine; SA, sialic acid; SO4, sulfate; Ser, serine and Thr, threonine.
Figure 3. Major types of glycoprotein. Cer, ceramide (N-fatty acyl sphingosine); Gal, d-galactose; Glc, d-glucose; GlcNH2, d-glucosamine; GlcNAc, N-acetyl-d-glucosamine; Man, mannose and PI, phosphatidylinositol.
Figure 4. Causes and consequences of altered epithelial glycosylation, using increased expression of galactose 13 N-acetylgalactosamine (Thomsen Friedenreich (TF) blood group antigen) as an example. (a) PNA histochemistry of colon cancer. The TF antigen (Gall-3GalNAc-) acts as an oncofetal carbohydrate antigen with increased expression in the normal fetus, in precancerous change and in cancer, shown here using peroxidase-conjugated (brown staining) TF-binding peanut lectin. (b) Changes in activity of any one of six enzymes could result in increased expression of oligosaccharide core type I (galactose 13 N-acetylgalactosamine ) TF antigen. 1, N-acetylglucosamine/N-acetylgalactosamine transferase (reduced activity results in preferential synthesis of type I core rather than type II (N-acetylglucosamine13galactosamine )); 2, N-acetylglucosamine to galactose transferase (reduced activity prevents more extensive glycosylation); 3, galactose to N-acetylgalactosamine transferase (increased activity leads to preferential type I expression); 4, galactose sulfotransferase (reduced activity leads to exposure of unsubstituted type I core); 5, galactose sialyl transferase (reduced activity leads to exposure of unsubstituted type I core) and 6, galactose fucosyl transferase (reduced activity leads to exposure of unsubstituted type I core). (c) Increased proliferation in response to peanut ingestion. This shows the rectal mitotic index (numbers of mitoses per crypt in endoscopic mucosalbiopsies) before and after a week of eating 100 g peanut per day by individuals who expressed the TF antigen in their rectal mucosa. This is confirmation of the hypothesis that altered epithelial glycosylation might allow interaction with intraluminal dietary or microbial lectins that would otherwise pass through the colon without interacting with the mucosa. This type of interaction can potentially be inhibited by nondigested oligosaccharides in vegetable fibre. From Ryder et al. (1998).
Figure 5. Congenital disorders of glycosylation and glycoforms. Glycoprotein isoforms or glycoforms differ based on N-glycan structures present at each NXS/T site. CDG type I has altered glycoform distribution due to deficiencies in Glc3Man9GlcNAc2-pp-dolichol biosynthesis, leading to incomplete N-X-S/T site occupancy. CDG type II results from deficiencies in Golgi remodelling or glycoprotein trafficking. Adapted from Dennis et al. (2009).
close
 References
    Agrawal B, Krantz MJ, Reddish MA and Longenecker BM (1998) Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2. Nature Medicine 4: 43–49.
    Bergström JP and Helander A (2008) Clinical characteristics of carbohydrate-deficient transferrin (%disialotransferrin) measured by HPLC: sensitivity, specificity, gender effects, and relationship with other alcohol biomarkers. Alcohol and Alcoholism 43: 436–441.
    Bresalier RS, Ho SB, Schoeppner HL et al. (1996) Enhanced sialylation of mucin-associated carbohydrate structures in human colon cancer metastasis. Gastroenterology 110: 1354–1367.
    Bresalier RS, Mazurek N, Sternber LR et al. (1998) Metastasis of human colon cancer is altered by modifying expression of the beta-galactoside-binding galectin-3. Gastroenterology 115: 287–296.
    Bruewer M, Samarin S and Nusrat A (2006) Inflammatory bowel disease and the apical junctional complex. Annals New York Academy Sciences 1072: 242–252.
    Conze T, Carvalho AS, Landegren U et al. (2010) MUC2 mucin is a major carrier of the cancer-associated sialyl-Tn antigen in intestinal metaplasia and gastric carcinomas. Glycobiology 20: 199–206.
    Corfield AP, Myersough N, Gough M et al. (1995) Glycosylation patterns of mucins in colonic disease. Biochemical Society Transactions 23: 840–845.
    Davril M, Degroote S, Humbert P et al. (1999) The sialylation of bronchial mucins secreted by patients suffering from cystic fibrosis or from chronic bronchitis is related to the severity of airway infection. Glycobiology 9: 311–321.
    Delmotte P, Degroote S, Lafitte JJ et al. (2002) Tumor necrosis factor alpha increases the expression of glycosyltransferases and sulfotransferases responsible for the biosynthesis of sialylated and/or sulfated Lewis x epitopes in the human bronchial mucosa. Journal of Biological Chemistry 277: 424–431.
    Dennis JW, Nabi IR and Demetriou M (2009) Metabolism, cell surface organisation and disease. Cell 139: 1229–1241.
    Freeze HH (2006) Genetic defects in the human glycome. Nature Reviews. Genetics 7: 537–551.
    Glinsky VV, Glinsky GV, Glinskii OV et al. (2003) Intravascular metastatic cancer cell homotypic aggregation at the sites of primary attachment to the endothelium. Cancer Research 63: 3805–3811.
    Glinsky VV, Huflejt ME, Glinsky GV, Deutscher SL and Quinn TP (2000) Effects of Thomsen-Friedenreich antigen-specific peptide P-30 on beta-galactoside-mediated homotypic aggregation and adhesion to the endothelium of MDA-MB-435 human breast carcinoma cells. Cancer Research 60: 2584–2588.
    Goupille C, Hallouin F, Meflah K and Le Pendu J (1997) Increase of rat colon carcinoma cells tumorigenicity by alpha(1-2) fucosyltransferase gene transfection. Glycobiology 7: 221–229.
    Granert C, Raud J, Xie X, Lindquist L and Lindbom L (1994) Inhibition of leukocyte rolling with polysaccharide fucoidin prevents pleocytosis in experimental meningitis in the rabbit. Journal of Clinical Investigation 93: 929–936.
    Haeuptle MA and Hennet T (2009) Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. Human Mutation 30: 1628–1641.
    Hakomori SI (2002) Inaugural article: the glycosynapse. Proceedings of the National Academy of Sciences of the USA 99: 225–232.
    Hakomori SI (2008) Structure and function of glycosphingolipids and sphingolipids: recollections and future trends. Biochimica et Biophysica Acta 1780: 325–346.
    Jaeken J, Hennet T, Freeze HH and Matthijs G (2008) On the nomenclature of congenital disorders of glycosylation (CDG). Journal of Inherited Metabolic Disease 31: 669–672.
    Jonckheere N and Van Seuningen I (2008) The membrane-bound mucins: how large O-glycoproteins play key roles in epithelial cancers and hold promise as biological tools for gene-based and immunotherapies. Critical Reviews in Oncogenesis 14: 177–196.
    Julien S, Picco G, Sewell R et al. (2009) Sialyl-Tn vaccine induces antibody-mediated tumour protection in a relevant murine model. British Journal of Cancer 100: 1746–1754.
    Karlen P, Young E, Brostrom O et al. (1998) Sialyl-Tn antigen as a marker of colon cancer risk in ulcerative colitis: relation to dysplasia and DNA aneuploidy. Gastroenterology 115: 1395–1404.
    Khaldoyanidi SK, Glinsky VV, Sikora L et al. (2003) MDA-MB-435 human breast carcinoma cell homo- and heterotypic adhesion under flow conditions is mediated in part by Thomsen-Friedenreich antigen-galectin-3 interactions. Journal of Biological Chemistry 278: 4127–4134.
    Kojima N, Fenderson BA, Stroud MR et al. (1994) Further studies on cell adhesion based on Lex–Lex interaction with new approaches: embryoglycan aggregation of F9 teratocarcinoma cells, and adhesion of various tumour cells based on Lex expression. Glycoconjugate Journal 11: 238–248.
    Kufe DW (2009) Mucins in cancer: function, prognosis and therapy. Nature Reviews. Cancer 9: 874–885.
    Lakhan SE, Sabharanjak S and De A (2009) Endocytosis of glycosylphosphatidylinositol-anchored proteins. Journal of Biomedical Science 16: 93.
    Lidell ME, Moncada DM, Chadee K et al. (2006) Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel. Proceedings of the National Academy of Sciences of the USA 103: 9298–9303.
    Limbergen JV, Russell RK, Nimmo ER et al. (2007) The genetics of inflammatory bowel disease. American Journal of Gastroenterology 102: 2820–2831.
    Linden SK, Sutton P, Karlsson NG et al. (2008) Mucins in the mucosal barrier to infection. Mucosal Immunology 1: 183–197.
    Liu FT and Rabinovich GA (2005) Galectins as modulators of tumour progression. Nature Reviews. Cancer 5: 29–41.
    Lopez PH and Schnaar RL (2009) Gangliosides in cell recognition and membrane protein regulation. Current Opinion in Structural Biology 19: 549–557.
    Lu MC, Hsieh SC, Lai NS et al. (2007) Comparison of anti-agalactosyl IgG antibodies, rheumatoid factors, and anti-cyclic citrullinated peptide antibodies in the differential diagnosis of rheumatoid arthritis and its mimics. Clinical and Experimental Rheumatology 25: 716–721.
    Mahdavi J, Sondén B, Hurtig M et al. (2002) Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science 297: 573–578.
    Malhotra R, Wormald MR, Rudd PM et al. (1995) Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein. Nature Medicine 1: 237–243.
    Marcos NT, Magalhães A, Ferreira B et al. (2008) Helicobacter pylori induces beta3GnT5 in human gastric cell lines, modulating expression of the SabA ligand sialyl-Lewis x. Journal of Clinical Investigation 118: 2325–2336.
    Marcos NT, Pinho S, Grandela C et al. (2004) Role of the human ST6GalNAc-I and ST6GalNAc-II in the synthesis of the cancer-associated sialyl-Tn antigen. Cancer Research 64: 7050–7057.
    Martin HM, Campbell BJ, Hart CA et al. (2004) Enhanced E. coli adherence and invasion in Crohn's disease and colon cancer. Gastroenterology 127: 80–93.
    Matthijs G, Schollen E, Pardon E et al. (1997) Mutations in PMMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome. Nature Genetics 16: 88–92.
    Mirelman D, Feingold C, Wexler A and Bracha R (1983) Interactions between Entamoeba histolytica, bacteria and intestinal cells. Ciba Foundation Symposium 99: 2–30.
    Morales-Serna JA, Boutureira O, Díaz Y, Matheu MI and Castillón S (2007) Recent advances in the glycosylation of sphingosines and ceramides. Carbohydrate Research 342: 1595–1612.
    Nangia-Makker P, Hogan V, Honjo Y et al. (2002) Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. Journal of the National Cancer Institute 94: 1854–1862.
    Nascimento de Araujo A and Giugliano LG (2000) Human milk fractions inhibit the adherence of diffusely adherent E. coli (DAEC) and enteroaggregative E. coli (EAEC) to HeLa cells. FEMS Microbiology Letters 84: 91–94.
    Nelson RM, Cecconi O, Roberts WG et al. (1993) Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation. Blood 82: 3253–3258.
    Ofek I, Hasty DL and Sharon N (2003) Anti-adhesion therapy of bacterial diseases: prospects and problems. FEMS Immunology and Medical Microbiology 38: 181–191.
    Ohkura T, Fukushima K, Kurisaki A et al. (1997) A partial deficiency of dehydrodolichol reduction is a cause of carbohydrate-deficient glycoprotein syndrome type 1. Journal of Biological Chemistry 272: 6868–6875.
    Pienta KJ, Naik H, Akhtar A et al. (1995) Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. Journal of the National Cancer Institute 87: 348–353.
    Pieters RJ (2007) Intervention with bacterial adhesion by multivalent carbohydrates. Medicinal Research Reviews 27: 796–816.
    Poschet J, Perkett E and Deretic V (2002) Hyperacidification in cystic fibrosis: links with lung disease and new prospects for treatment. Trends in Molecular Medicine 8: 512–519.
    Rabinovich GA, Toscano MA, Jackson SS and Vasta GR (2007) Functions of cell surface galectin-glycoprotein lattices. Current Opinion in Structural Biology 17: 513–520.
    Raza MW, Blackwell CC, Molyneux P et al. (1991) Association between secretor status and respiratory viral illness. British Medical Journal 303: 815–818.
    Regina Todeschini A and Hakomori SI (2008) Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochimica et Biophysica Acta 1780: 421–433.
    Rhee SH, Im E, Riegler M et al. (2005) Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation. Proceedings of the National Academy of Sciences of the USA 102: 13610–13615.
    Rhodes JM (1996) Unifying hypothesis for inflammatory bowel disease and related colon cancer: sticking the pieces together with sugar. Lancet 347: 40–44.
    Rhodes JM, Campbell BJ and Yu LG (2008) Lectin-epithelial interactions in the human colon. Biochemical Society Transactions 36: 1482–1486.
    Ryder SD, Jacyna MR, Levi AJ, Rizzi PM and Rhodes JM (1998) Eating peanuts increases rectal proliferation in individuals with mucosal expression of peanut lectin receptor. Gastroenterology 114: 44–49.
    Svensson M, Platt FM and Svanborg C (2006) Glycolipid receptor depletion as an approach to specific antimicrobial therapy. FEMS Microbial Letters 258: 1–8.
    Thomas JR, Dwek RA and Rademacher TW (1990) Structure, biosynthesis and function of glycosylphosphatidylinositols. Biochemistry 29: 5413–5422.
    Thornton DJ, Rousseau K and McGuckin MA (2008) Structure and function of the polymeric mucins in airways mucus. Annual Review of Physiology 70: 459–486.
    Variyam EP (2007) Luminal host-defense mechanisms against invasive amebiasis. Trends in Parasitology 23: 108–111.
    Vavasseur F, Dole K, Yang J et al. (1994) O-glycan biosynthesis in human colorectal adenoma cells during progression to cancer. European Journal of Biochemistry 222: 415–424.
    Vázquez-Martín C, Cuevas E, Gil-Martín E and Fernández-Briera A (2004) Correlation analysis between tumor-associated antigen sialyl-Tn expression and ST6GalNAc I activity in human colon adenocarcinoma. Oncology 67: 159–165.
    Von Itzstein M, Wu WY, Kok GB et al. (1993) Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363: 418–423.
    Yoshimura M, Ihara Y, Matsuzawa Y and Taniguchi N (1996) Aberrant glycosylation of E-cadherin enhances cell–cell binding to suppress metastasis. Journal of Biological Chemistry 271: 13811–13815.
    Yu LG, Andrews N, Weldon M et al. (2002) An N-terminal truncated form of Orp150 is a cytoplasmic ligand for the anti-proliferative mushroom Agaricus bisporus lectin and is required for NLS-dependent nuclear protein import. Journal of Biological Chemistry 277: 24538–24545.
    Yu LG, Andrews N, Zhao Q et al. (2007) Galectin-3 interaction with Thomsen-Friedenreich oligosaccharide on cancer-associated MUC1 causes increased cancer cell-endothelial adhesion. Journal of Biological Chemistry 282: 773–781.
    Yu LG, Fernig DG, White MRH et al. (1999) Edible mushroom (Agaricus bisporus) lectin, which reversibly inhibits epithelial cell proliferation, blocks NLS-dependent nuclear protein import. Journal of Biological Chemistry 274: 4890–4899.
    Yuki N, Susuki K, Koga M et al. (2004) Carbohydrate mimicry between human ganglioside GM1 and Campylobacter jejuni lipooligosaccharide causes Guillain-Barre syndrome. Proceedings of the National Academy of Sciences of the USA 101: 11404–11409.
    Zhao Q, Guo X, Stone P et al. (2009) Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface. Cancer Research 69: 6799–6806.
    Zhao Y, Sato Y, Isaji T et al. (2008) Branched N-glycans regulate the biological functions of integrins and cadherins. FEBS Journal 275: 1939–1948.
    Zheng M, Fang H and Hakomori S (1994) Functional role of N-glycosylation in a5b1 integrin receptor: de-N-glycosylation induces dissociation or altered association of a5 and b1 subunits and concomitant loss of fibronectin binding activity. Journal of Biological Chemistry 269: 12325–12331.
 Further Reading
    Brockhausen I (2006) Mucin-type O-glycans in human colon and breast cancer: glycodynamics and functions. EMBO Reports 7: 599–604.
    Iurisci I, Tinari N, Natoli C et al. (2000) Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clinical Cancer Research 6: 1389–1393.
    Jensen PH, Kolarich D and Packer NH (2010) Mucin-type O-glycosylation–putting the pieces together. FEBS Journal 277: 81–94.
    Karlsson K-A (1998) Meaning and therapeutic potential of microbial recognition of host glycoconjugates. Molecular Microbiology 29: 1–11.
    Li H and d'Anjou M (2009) Pharmacological significance of glycosylation in therapeutic proteins. Current Opinion in Biotechnology 20: 678–684.
    Patsos G, Robbe-Masselot C, Klein A et al. (2007) O-glycan regulation of apoptosis and proliferation in colorectal cancer cell lines. Biochemical Society Transactions 35(Pt 5): 1372–1374.
    Rhodes JM (1997) Mucins and inflammatory bowel disease. Quarterly Journal of Medicine 90: 79–82.
    book Varki A, Cummings R, Esko J et al. (eds) (1999) Essentials of Glycobiology. New York: Cold Spring Harbor Laboratory Press.

Related Sub-Topics:

Infection | Inflammation | Tumour Immunology | Structure of Cell–Cell Interactions | Protein Structure | Lipids and Membrane Structure | Biomolecular Interactions | Proteins: Structure, Function, Metabolism | Lipids: Structure, Function, Metabolism
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Glycosylation and Disease
 
How to Cite close
Rhodes, Jonathan, Campbell, Barry J, and Yu, Lu‐Gang(Sep 2010) Glycosylation and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002151.pub2]