| Structure of proteoglycans
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| The general structures of the glycosaminoglycans (GAGs), the carbohydrate part of the proteoglycans, are shown in Table 27.2. The disaccharide repeat is different for each type of GAG, but is usually composed of a hexosamine and a uronic acid residue, except in the case of keratan sulfate, in which the uronic acid is replaced by galactose. The amino sugar in GAGs is either glucosamine (GlcNH2) or galactosamine (GalNH2), both of which are present mostly in their N-acetylated forms (GlcNAc and GalNAc), although in some of the GAGs (heparin, heparan sulfate) the amino group is sulfated, rather than acetylated. The uronic acid is usually d-glucuronic acid (GlcUA), but in some cases (dermatan sulfate, heparin) it may be l-iduronic acid (IdUA). With the exception of hyaluronic acid and keratan sulfate, all of the GAGs are attached to protein by a core trisaccharide, Gal-Gal-Xyl, attached to a serine or threonine residue of a core protein. Keratan sulfate is also attached to protein, but in that case the linkage is either through an N-linked oligosaccharide (keratan sulfate I), or an O-linked oligosaccharide (keratan sulfate II). Hyaluronic acid, which has the longest polysaccharide chains, is the only GAG that does not appear to be attached to a core protein.
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| Hyaluronic acid is composed of repeating units of GlcNAc and GlcUA. This polysaccharide chain is the longest of the GAGs, with molecular weight of 105-107 Da (250-25 000 repeating disaccharide units), and is the only nonsulfated GAG.
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| The chondroitin sulfates are major components of cartilage. They contain GalNAc rather than GlcNAc as the amino sugar, and their polysaccharide chains are shorter: 2-5 × 105 Da. The chondroitin chains are attached to protein via the trisaccharide linkage region (Gal-Gal-Xyl), and they contain sulfate residues linked to either the 4- or 6-hydroxyl groups of GalNAc.
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| Dermatan sulfate was originally isolated from skin, but is also found in blood vessels, tendon and heart valves. This GAG is similar in structure to chondroitin sulfate, but has a variable amount of l-IdUA, the C-5-epimer of d-GlcUA, formed in an unusual reaction by epimerization of GlcUA after it has been incorporated into the polymer. Dermatan sulfate has a higher charge density than the chondroitin sulfates, as it contains sulfate residues on the C-2 position of some IdUA residues, and on the 4-hydroxyl groups of GalNAc.
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| Heparin and heparan sulfate
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| Heparin and heparan sulfate consist primarily of repeating disaccharide units of GlcNH2 with IdUA or GlcUA, respectively. The linkage between the amino sugar and the uronic acid is uniformly 1-4, rather than the alternating 1-4/1-3 linkages seen in other GAGs. Most of the GlcNH2 units of
heparin are N-sulfated, whereas many of the IdUA residues are sulfated at the C-2 hydroxyl group, and the GlcNH2 residues at the C-6 hydroxyl group. Heparin and heparan sulfate are the most highly charged of the GAGs. Although the structures of these two polymers are closely related, their distribution in the body and their functions are quite different: heparin is a small microheterogeneous molecule (∼3,000-30 000 Da), found intracellularly as a proteoglycan. It is released into the extracellular space as a glycosaminoglycan, and has strong anticoagulant activity. In contrast, heparan sulfate is bound in the ECM or on the surface of cells, and has only weak anticoagulant activity.
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| The final GAG structure shown in Table 27.2 is keratan sulfate (KS). This is a rather unusual GAG because it is linked to protein either by an N-linked (KS I), or by an O-linked (KS II) oligosaccharide. Thus it has features common to both proteoglycans and glycoproteins. It is considered to be a proteoglycan, however, because the glycan portion has a repeating disaccharide unit and a long, linear chain. The repeating unit is composed of GlcNAc and galactose in place of the uronic acid. Both the GlcNAc and the galactose are generally sulfated on the C-6 hydroxyl groups.
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