At least four subclasses of O-glycosidic linkages are found in human glycoproteins:

1. The N-acetylgalactosamine-Ser(Thr) linkage shown in Figure 1 is the predominant linkage. Usually a galactose or an N-acetylneuraminic acid residue is attached to the N-acetylgalactosamine, but many variations in the sugar compositions and lengths of such oligosaccharide chains are found. This type of linkage is found in mucins .

2. Proteoglycans contain a galactose-galactose-xylose tri saccharide (the so-called link trisaccharide) attached to serine.

3. Collagens contain a galactose-hydroxy lysine linkage.

4. Many nuclear and cytosolic proteins contain side chains consisting of a single N-acetylglucosamine attached to a serine or threonine residue.

Fig1. The three main types of glycoprotein: (A) anO-linkage (N-acetylgalactosamine to serine), (B) an N-linkage (N-acetylglucosamine to asparagine), and (C) a glycosylphosphatidylinositol (GPI) linkage. The GPI structure shown is that linking acetylcholinesterase to the plasma membrane of the human red blood cell. The site of action of PI-phospholipase C (PI-PLC), which releases the enzyme from membrane binding is indicated. This particular GPI contains an extra fatty acid attached to inositol and also an extra phosphoryl ethanolamine moiety attached to the central of the mannose residue. Variations found among different GPI structures include the identity of the carboxyl-terminal amino acid, the molecules attached to the mannose residues, and the precise nature of the lipid moiety.

Mucins Have a High Content of O-Linked Oligosaccharides & Exhibit Repeating Amino Acid Sequences

Mucins are glycoproteins that are highly resistant to proteolysis because the density of oligosaccharide chains makes it difficult for proteases to access the polypeptide chain. They help to lubricate and form a protective physical barrier on epithelial surfaces.

Mucins have two distinctive characteristics: a high con tent of O-linked oligosaccharides (the carbohydrate content is generally more than 50%); and the presence of variable numbers of tandem repeats (VNTRs) of peptide sequence in the center of the polypeptide chain, to which the O-glycan chains are attached in clusters. These tandem repeat sequences are rich in serine, threonine, and proline; indeed, up to 60% of the dietary requirement for threonine can be accounted for by the synthesis of mucins. Although O-glycans predominate, mucins often also contain a number of N-glycan chains.

Both secretory and membrane-bound mucins occur. Mucus secreted by the gastrointestinal, respiratory, and reproductive tracts is a solution containing about 5% mucins. Secretory mucins generally have an oligomeric structure, with monomers linked by disulfide bonds, and hence a very high molecular mass. Mucus has a high viscosity and often forms a gel because of its content of mucins. The high content of O-glycans confers an extended structure. This is partly explained by steric interactions between the N-acetylgalactosamine moieties and adjacent amino acids, resulting in a chain-stiffening effect, so that the con formation of mucins often become rigid rods. Intermolecular noncovalent interactions between sugars on neighboring glycan chains contribute to gel formation. The high content of N-acetylneuraminic acid and sulfate residues found in many mucins gives them a negative charge.

Membrane-bound mucins participate in cell–cell inter actions. They may also mask cell surface antigens. Many cancer cells form large amounts of mucins that mask surface antigens and protect the cancer cells from immune surveil lance. Mucins also carry cancer-specific peptide and carbohydrate epitopes. Some of these have been used to stimulate an immune response against cancer cells.

O-Linked Glycoproteins Are Synthesized by Sequential Addition of Sugars from Sugar Nucleotides

 Because most glycoproteins are membrane-bound or secreted, their mRNA is usually translated on membrane-bound poly ribosomes. The glycan chains are built up by the sequential donation of sugars from sugar nucleotides, catalyzed by glycoprotein glycosyltransferases. Because many glycosylation reactions occur within the lumen of the Golgi apparatus, there are carrier systems (permeases and transporters) to transport sugar nucleotides (UDP-galactose, GDP-mannose, and CMP-N-acetylneuraminic acid) across the Golgi membrane. These are antiporter systems in which the influx of one molecule of sugar nucleotide is balanced by the efflux of one molecule of the corresponding nucleotide (UMP, GMP, or CMP).

Humans possess 41 different types of glycoprotein glycosyltransferases. Families of glycosyltransferases are named for the sugar nucleotide donor, and subfamilies on the basis of the linkage formed between the sugar and the acceptor substrate; transfer may occur with retention or inversion of the conformation at C-1 of the sugar. Binding of the sugar nucleotide to the enzyme causes a conformational change in the enzyme that permits binding of the acceptor substrate. Glycosyltransferases show a high degree of specificity for the acceptor substrate, typically acting only on the product of the preceding reaction. The different stages in glycan formation, and hence the different glycosyltransferases, are located in different regions of the Golgi, which provides for spatial separation of the steps in the process. Not all of the glycan chains of a given glycoprotein are complete; some are truncated, leading to microheterogeneity. No consensus sequence is known to determine which serine and threonine residues are glycosylated, but the first sugar moiety incorporated is usually N-acetylgalactosamine.

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