Glycosylation and Disease

Abstract

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 β1→3 N‐acetylgalactosamine α(Thomsen Friedenreich (TF) blood group antigen) as an example. (a) PNA histochemistry of colon cancer. The TF antigen (Galβl‐3GalNAcα‐) 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 β1→3 N‐acetylgalactosamine α) TF antigen. 1, N‐acetylglucosamine/N‐acetylgalactosamine transferase (reduced activity results in preferential synthesis of type I core rather than type II (N‐acetylglucosamineβ1→3galactosamine α)); 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. .

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..

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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]