Glycosaminoglycans, Proteoglycans, and Glycoproteins

Transcription

1 Glycosaminoglycans, Proteoglycans, and Glycoproteins Presented by Dr. Mohammad Saadeh The requirements for the Pharmaceutical Biochemistry I Philadelphia University Faculty of pharmacy

2 I. OVERVIEW OF GLYCOSAMINOGLYCANS They are generally associated with a small amount of protein, forming proteoglycans, which typically consist of over 95% carbohydrate. The viscous, lubricating properties of mucous secretions are also caused by the presence of glycosaminoglycans, which led to the original naming of these compounds as mucopolysaccharides. As essential components of cell surfaces, glycosaminoglycans play an important role in mediating cell cell signaling and adhesion.

3 II. Structure of Glycosaminoglycans *Glycosaminoglycans (GAGs) are long, negatively charged, unbranched, heteropolysaccharide chains generally composed of a repeating disaccharide unit [acidic sugar amino sugar]n (Figure 14.18). *The amino sugar is either D-glucosamine or D- galactosamine in which the amino group is usually acetylated, thus eliminating its positive charge. The amino sugar may also be sulfated on carbon 4 or 6 or on a nonacetylated nitrogen. *The acidic sugar is either D-glucuronic acid or its C-5 epimer, L-iduronic acid that is contain carboxyl groups that are negatively charged at physiologic ph and, together with the sulfate groups, give GAGs their strongly negative nature. * These compounds bind large amounts of water, thereby producing the gel-like matrix that forms the basis of the body s ground substance. Figure 14.1 Repeating disaccharide unit. Figure 14.2, Some monosaccharide units found in glycosaminoglycans

4 II. Structure of Glycosaminoglycans A. Relationship between glycosaminoglycan (GAGs) structure and function *Negative charges of heteropolysaccharide chains tend to be extended in solution. They repel each other, and are surrounded by a shell of water molecules. *When a solution of GAGs is compressed, the water is squeezed out and the glycosaminoglycans are forced to occupy a smaller volume. *When the compression is released (relax), the GAGs spring back to their original, hydrated volume because of the repulsion of their negative charges. This property contributes to the resilience of synovial fluid and the vitreous humor of the eye (Figure 14.3). Figure 14.3, Resilience of glycosaminoglycans.

5 II. Structure of Glycosaminoglycans B. Classification of the glycosaminoglycans (GAGs) * Glycosaminoglycans are divided to the six major classes (Figure 14.4). according to, 1. monomeric composition. 2. type of glycosidic linkages. 3. degree and location of sulfate units. The structure of the glycosaminoglycans and their distribution in the body is illustrated in (Figure 14.4).

6 II. Structure of Glycosaminoglycans; B. Classification of the glycosaminoglycans

7 II. Structure of Glycosaminoglycans C. Proteoglycans Proteoglycans are found in the extracellular matrix. 1. Structure of proteoglycan monomers: * proteoglycan monomer, is linear GAGs chains (Chondroitin sulfate and keratan sulfate) are covalently attached to core protein. these monomer bonded with hyaluronic acid through ionic interaction and stabilize by link proteins. * Each chains, composed of more than 100 monosaccharides, extend out from the core protein, and remain separated from each other because of charge repulsion. The resulting structure resembles a bottle brush (Figure 14.5). Figure 14.5 "Bottle-brush" model of a cartilage proteoglycan monomer.

8 II. Structure of Glycosaminoglycans C. Proteoglycans 2. Linkage between the carbohydrate chain and the protein: This linkage through a trihexoside (galactose-galactosexylose) and a serine residue, respectively. An O-glycosidic bond is formed between the xylose and the hydroxyl group of the serine (Figure 14.6). Figure 14.6, Linkage region of glycosaminoglycans.

9 II. Structure of Glycosaminoglycans C. Proteoglycans 3. Proteoglycan aggregates: proteoglycan monomers aggregates through ionic interactions between the core protein and the hyaluronic acid to form proteoglycan aggregates. The association is stabilized by additional small proteins called link proteins (Figure 14.7). Figure 14.7, proteoglycan monomers aggregates

10 VI. Overview of Glycoproteins Glycoproteins are proteins to which oligosaccharides are covalently attached. They differ from the proteoglycans in that the length of the glycoprotein s carbohydrate chain is relatively short. Glycoproteins contain highly variable amounts of carbohydrate. For example, immunoglobulin IgG (<4%), human gastric glycoprotein (mucin) >80%. Membrane-bound glycoproteins participate in a broad range of cellular phenomena, including 1. Cell surface recognition (by other cells, hormones, and viruses), 2. Cell surface antigenicity (such as the blood group antigens). 3. Components of the extracellular matrix. 4. Components of the mucins of the gastrointestinal and urogenital tracts, where they act as protective biologic lubricants. 5. almost all of the globular proteins present in human plasma are glycoproteins. (See Figure 14.13: for a summary of some of the functions of glycoproteins.)

11 Figure Functions of glycoproteins.

12 VII. Oligosaccharides The oligosaccharide components of glycoproteins are generally branched heteropolymers composed primarily of D-hexoses, with the addition in some cases of neuraminic acid, and of L-fucose, a 6-deoxyhexose. A. Structure of the linkage between carbohydrate and protein The oligosaccharide attached to the protein through an N- or an O-glycosidic link. Example: 1. the sugar chain is attached to the amide group of an asparagine side chain. 2. the hydroxyl group of either a serine or threonine R-group (see Figure). Figure: Glycosides: examples of N- and O-glycosidic bonds.

13 VII. OLIGOSACCHARIDES B. N- and O-linked oligosaccharides: A glycoprotein may contain only one type of glycosidic linkage (N- or O-linked), or may have both O- and N-linked oligosaccharides within the same molecule. 1. O-Linked oligosaccharides: Many O-linked oligosaccharides are found in extracellular glycoproteins or as membrane glycoprotein components. For example, O- linked oligosaccharides on the surface of RBCs help provide the ABO blood group determinants (See figure 11-12). Human blood groups (A, B, O)

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15 VII. OLIGOSACCHARIDES 2. N-linked oligosaccharides: The N-linked oligosaccharides fall into two broad classes: complex oligosaccharides high-mannose oligosaccharides. Both contain the same core penta saccharide shown in Figure 14.14, but the complex oligosaccharides contain a diverse group of additional sugars, for example, GlcNAc, L- fucose, and NANA, whereas the highmannose oligosaccharides contain primarily mannose. Figure Complex (top) and high-mannose (bottom) oligosaccharides. [Note: Members of each class contain the same pentasaccharide core.] NANA= N-acetylneuramic acid; Gal= galactose; GlcNAc=N-acetyleglucosamine; Man=mannose; Fuc=fucose; Asn=Asparagine.

16 Summary: Glycosaminoglycans are long, negatively charged, unbranched, hetero polysaccharide chains generally composed of a repeating disaccharide unit [acidic sugar amino sugar]n (Figure 14.18). The amino sugar is either Dglucosamine or D-galactosamine in which the amino group is usually acetylated, thus eliminating its positive charge. The amino sugar may also be sulfated on carbon 4 or 6 or on a nonacetylated nitrogen. The acidic sugar is either D-glucuronic acid or its C-5 epimer, L-iduronic acid. These compounds bind large amounts of water, thereby producing the gel-like matrix that forms the basis of the body s ground substance. The viscous, lubricating properties of mucous secretions are also caused by the presence of glycosaminoglycans, which led to the original naming of these compounds as mucopolysaccharides. As essential components of cell surfaces, glycosaminoglycans play an important role in mediating cell cell signaling and adhesion. There are six major classes of glycosaminoglycans, including chondroitin 4- and 6-sulfates, keratan sulfate, dermatan sulfate, heparin, heparan sulfate, and hyaluronic acid. All of the glycosaminoglycans, except hyaluronic acid, are found covalently attached to protein, forming proteoglycan monomers, which consist of a core protein to which the linear glycosaminoglycan chains are covalently attached. The proteoglycan monomers associate with a molecule of hyaluronic acid to form proteoglycan aggregates. Glycosaminoglycans are synthesized in the Golgi. Glycoproteins are proteins to which oligosaccharides are covalently attached. They differ from the proteoglycans in that the length of the glycoprotein s carbohydrate chain is relatively short (usually two to ten sugar residues long, although they can be longer), may be branched, and does not contain serial disaccharide units. Membrane-bound glycoproteins participate in a broad range of cellular phenomena, including cell surface recognition (by other cells, hormones, and viruses), cell surface anti genicity (such as the blood group antigens), and as components of the extracellular matrix and of the mucins of the gastrointestinal and urogenital tracts, where they act as protective biologic lubricants. In addition, almost all of the globular proteins present in human plasma are glycoproteins.

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