The Various Glycosaminoglycans Exhibit Differences in Structure Have Characteristic Distributions

The seven GAGs named above differ from each other in a number of the following properties: amino sugar composition, uronic acid composition, linkages between these components, chain length of the disaccharides, the presence or absence of sulfate groups and their positions of attachment to the constituent sugars, the nature of the core proteins to which they are attached, the nature of the linkage to core protein, their tissue and subcellu-lar distribution, and their biologic functions.

The structures (Figure 48-8) and the distributions of each of the GAGs will now be briefly discussed. The major features of the seven GAGs are summarized in Table 48-6.

A. Hyaluronic Acid_

Hyaluronic acid consists of an unbranched chain of repeating disaccharide units containing GlcUA and Glc-NAc. Hyaluronic acid is present in bacteria and is widely distributed among various animals and tissues, including synovial fluid, the vitreous body of the eye, cartilage, and loose connective tissues.

B. Chondroitin Sulfates (Chondroitin 4-Sulfate & Chondroitin 6-Sulfate)_

Proteoglycans linked to chondroitin sulfate by the Xyl-Ser O-glycosidic bond are prominent components of cartilage (see below). The repeating disaccharide is similar to that found in hyaluronic acid, containing

Hyaluronic acid Link protein

Keratan sulfate

Chondroitin sulfate

Core protein

Subunits

Figure 48-7. Schematic representation of the proteoglycan aggrecan. (Reproduced, with permission, from Lennarz WJThe Biochemistry of Glycoproteins and Proteoglycans. Plenum Press, 1980.)

Hyaluronic acid:

Chondroitin sulfates: -¡-U- GlcUA GalNAc GlcUA -i»1^- Gal Gal Xyl Ser

4- or 6-Sulfate

Keratan sulfates I and II:

GlcNAc Gal ^ GlcNAc Gal

- GlcNAc p> Asn (keratan sulfate I)

6-Sulfate 6-Sulfate "--GalNAc-^-Thr (Ser) (keratan sulfate II)

Gal-NeuAc

Heparin and heparan sulfate:

6-Sulfate

^ IdUA GlcN ^ GlcUA ^ GlcNAc GlcUA ^ Gal ^ Gal »V Xyl Ser

2-Sulfate SO3- or Ac

Dermatan sulfate: IdUA—GalNAc -¡--U- GlcUAGalNAc GlcUAGal Gal -¡--U- Xyl Ser

2-Sulfate 4-Sulfate

Figure 48-8. Summary of structures of glycosaminoglycans and their attachments to core proteins. (GlcUA, D-glucuronic acid; IdUA, L-iduronic acid; GlcN, D-glucosamine; GalN, D-galactosamine; Ac, acetyl; Gal, D-galac-tose; Xyl, D-xylose; Ser, L-serine; Thr, L-threonine; Asn, L-asparagine; Man, D-mannose; NeuAc, W-acetylneu-raminic acid.) The summary structures are qualitative representations only and do not reflect, for example, the uronic acid composition of hybrid glycosaminoglycans such as heparin and dermatan sulfate, which contain both L-iduronic and D-glucuronic acid. Neither should it be assumed that the indicated substituents are always present, eg, whereas most iduronic acid residues in heparin carry a 2'-sulfate group, a much smaller proportion of these residues are sulfated in dermatan sulfate. The presence of link trisaccharides (Gal-Gal-Xyl) in the chondroitin sulfates, heparin, and heparan and dermatan sulfates is shown. (Slightly modified and reproduced, with permission, from Lennarz WJ: The Biochemistry of Glycoproteins and Proteoglycans. Plenum Press, 1980.)

Table48-6. Major properties of the glycosaminoglycans.

GAG

Sugars

Sulfate1

Linkage of Protein

Location

HA

GIcNAc, GlcUA

Nil

No firm evidence

Synovial fluid, vitreous humor, loose connective tissue

CS

GalNAc, GlcUA

GalNAc

Xyl-Ser; associated with

HA via link proteins

Cartilage, bone, cornea

KS I

GlcNAc, Gal

GlcNAc

GlcNAc-Asn

Cornea

KS II

GlcNAc, Gal

Same as KS I

GalNAc-Thr

Loose connective tissue

Heparin

GlcN, IdUA

GlcN

Ser

Mast cells

GlcN

IdUA

Heparan sulfate

GlcN, GlcUA

GlcN

Xyl-Ser

Skin fibroblasts, aortic wall

Dermatan

GalNAc, IdUA,

GaINAc

Xyl-Ser

Wide distribution

sulfate

(GlcUA)

IdUa

1The sulfate is attached to various positions of the sugars indicated (see Figure 48-7).

1The sulfate is attached to various positions of the sugars indicated (see Figure 48-7).

GlcUA but with GalNAc replacing GlcNAc. The GalNAc is substituted with sulfate at either its 4' or its 6' position, with approximately one sulfate being present per disaccharide unit.

C. Keratan Sulfates I & II_

As shown in Figure 48-8, the keratan sulfates consist of repeating Gal-GlcNAc disaccharide units containing sulfate attached to the 6' position of GlcNAc or occasionally of Gal. Type I is abundant in cornea, and type II is found along with chondroitin sulfate attached to hyaluronic acid in loose connective tissue. Types I and II have different attachments to protein (Figure 48-8).

D. Heparin_

The repeating disaccharide contains glucosamine (GlcN) and either of the two uronic acids (Figure 48-9). Most of the amino groups of the GlcN residues are N-sulfated, but a few are acetylated. The GlcN also carries a C6 sulfate ester.

Approximately 90% of the uronic acid residues are IdUA. Initially, all of the uronic acids are GlcUA, but a 5'-epimerase converts approximately 90% of the GlcUA residues to IdUA after the polysaccharide chain is formed. The protein molecule of the heparin proteoglycan is unique, consisting exclusively of serine and glycine residues. Approximately two-thirds of the serine residues contain GAG chains, usually of 5-15 kDa but occasionally much larger. Heparin is found in the granules of mast cells and also in liver, lung, and skin.

E. Heparan Sulfate_

This molecule is present on many cell surfaces as a proteoglycan and is extracellular. It contains GlcN with fewer N-sulfates than heparin, and, unlike heparin, its predominant uronic acid is GlcUA.

F. Dermatan Sulfate_

This substance is widely distributed in animal tissues. Its structure is similar to that of chondroitin sulfate, ex cept that in place of a GlcUA in P-1,3 linkage to GalNAc it contains an IdUA in an a-1,3 linkage to GalNAc. Formation of the IdUA occurs, as in heparin and heparan sulfate, by 5'-epimerization of GlcUA. Because this is regulated by the degree of sulfation and because sulfation is incomplete, dermatan sulfate contains both IdUA-GalNAc and GlcUA-GalNAc ¿saccharides.

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