Heteropolysaccharides: Glycosaminoglycans:
One group of polysaccharides is of major structural importance in vertebrate animals—the glycosaminoglycans,formerly called mucopolysaccharides. Important examples are the chondroitin sulfates and keratan sulfates of connective tissue, the dermatan sulfates of skin, and hyaluronic acid. All are polymers of repeating disaccharide units, in which one of the sugars is either N-acetylgalactosamine or N-acetylglucosamine or one of their derivatives. All are acidic, through the presence of either sulfate or carboxylate groups. Hyaluronic acid (hyaluronate) is an important glycosaminoglycan component of connective tissue, synovial fluid (the fluid that lubricates joints), and the vitreous humor of the eye. In most mammals, hyaluronate molecules are composed of 80 to 8000 ´(1→4)-linked disaccharide units that consist of D-glucuronic acid and N-acetyl-D-glucosamine (GlcNAc) linked by a ´(1→3) bond (Fig. 8-12). Hyaluronate is an extended, rigid molecule whose numerous repelling anionic groups bind cations and water molecules.
In solution, hyaluronate occupies a volume ∼1000 times that in its dry state. Hyaluronan is also a component of the extracellular matrix of cartilage and tendons, to which it contributes tensile strength and elasticity as a result of its strong noncovalent interactions with other components of the matrix. Hyaluronidase, an enzyme secreted by some pathogenic bacteria, can hydrolyze the glycosidic linkages of hyaluronan, rendering tissues more susceptible to bacterial invasion. In many animal species, a similar enzyme in sperm hydrolyzes an outer glycosaminoglycan coat around the ovum, allowing sperm penetration.
Hyaluronate has an unanticipated property. The naked mole rat is a hairless, mouse-sized rodent (it resembles a pink sausage with teeth) that has a longer life span (>30 years) than any other rodent. This is, in part, because cancer has never been observed in naked mole rats (in contrast, mice and rats, which live ∼4 years, have a high incidence of cancer). Naked mole rat cells secrete extremely high molecular mass hyaluronate; it consists of 16 to 32 thousand disaccharide units. This interferes with the signaling pathways that support malignant transformation. Consequently, reducing the amount of high molecular-mass hyaluronate in a culture of naked mole rat cells by either mutationally under-expressing the enzyme that synthesizes the hyaluronate or overexpressing the enzyme that degrades it yields cells that are susceptible to malignant transformation. The other common glycosaminoglycans shown in Fig. 8-12 consist of 50 to 1000 sulfated disaccharide units. These glycosaminoglycans differ from hyaluronan in three respects: they are generally much shorter polymers, they are covalently linked to specific proteins (proteoglycans), and one or both monomeric units differ from those of hyaluronan.
Chondroitin sulfate (Greek chondros, <cartilage=) contributes to the tensile strength of cartilage, tendons, ligaments, and the walls of the aorta. Chondroitin- 4-sulfate and chondroitin-6-sulfate differ only in the sulfation of their N-acetylgalactosamine (GalNAc) residues.
Dermatan sulfate (Greek derma, <skin=) is derived from chondroitin by enzymatic epimerization of the C5 of glucuronate residues to form iduronate residues. Dermatan sulfate contributes to the pliability of skin and is also present in blood vessels and heart valves. In this polymer, many of the glucuronate residues present in chondroitin sulfate are replaced by their 5-epimer, L-iduronate (IdoA).
Keratan sulfate (Greek keras, <horn=) (not to be confused with the fibrous protein keratin) is the most
heterogeneous of the major glycosaminoglycans in that its sulfate content is variable and it contains small amounts of fucose, mannose, GlcNAc, and sialic acid. Keratan sulfates have no uronic acid and their sulfate content is variable. They are present in cornea, cartilage, bone, and a variety of horny structures formed of dead cells: horn, hair, hoofs, nails, and claws.
Heparin is a fractionated form of heparan sulfate derived mostly from mast cells (a type of leukocyte). Heparin is the most highly charged polymer in mammalian tissues. In contrast to the other glycosaminoglycans, heparin is not a constituent of connective tissue but occurs almost exclusively in the intracellular granules of the mast cells that occur in arterial walls. It inhibits the clotting of blood, and its release, through injury, is thought to prevent runaway clot formation. Heparin is therefore in wide clinical use to inhibit blood clotting—for example, in postsurgical patients. Heparin binding causes antithrombin to bind to and inhibit thrombin, a protease essential to blood clotting. The interaction is strongly electrostatic; heparin has the highest negative charge
density of any known biological macromolecule. Purified heparin is routinely added to blood samples obtained for clinical analysis, and to blood donated for transfusion, to prevent clotting.
Heparan sulfate (Greek h¯epar, <liver=; it was originally isolated from dog liver) is produced by all animal cells and contains variable arrangements of sulphated and non-sulfated sugars. It is a ubiquitous cell-surface component as well as an extracellular substance in blood vessel walls and brain. Heparan sulfate resembles heparin but has a far more variable composition, with fewer N- and O-sulfate groups and more N-acetyl groups. Heparan sulfate plays a critical role in development and in wound healing. Various growth factors bind to heparan sulfate, and the formation of complexes of the glycosaminoglycan, the growth factor, and the growth factor receptor is required to initiate cell differentiation and proliferation. Specific sulfation patterns on heparan sulfate are required for the formation of these ternary complexes.
Glycoconjugates
In addition to their important roles as stored fuels (starch, glycogen, dextran) and as structural materials
(cellulose, chitin, peptidoglycans), polysaccharides and oligosaccharides are information carriers. Some provide communication between cells and their extracellular surroundings; others label proteins for transport to and localization in specific organelles, or for destruction when the protein is malformed or superfluous; and others serve as recognition sites for extracellular signal molecules (growth factors, for example) or extracellular parasites (bacteria or viruses). On almost every eukaryotic cell, specific oligosaccharide chains attached to components of the plasma membrane form a carbohydrate layer (the glycocalyx), several nanometers thick, that serves as an information-rich surface that the cell shows to its surroundings. These oligosaccharides are central players in cell-cell recognition and adhesion, cell migration during development, blood clotting, the immune response, wound healing, and other cellular processes. In most of these cases, the informational carbohydrate is covalently joined to a protein or a lipid to form a glycoconjugate, which is the biologically active molecule.
Proteoglycans are macromolecules of the cell surface or extracellular matrix in which one or more sulphated glycosaminoglycan chains are joined covalently to a membrane protein or a secreted protein. The glycosaminoglycan chain can bind to extracellular proteins through electrostatic interactions between the protein and the negatively charged sugar moieties on the proteoglycan. Proteoglycans are major components of all extracellular matrices.
Glycoproteins have one or several oligosaccharides of varying complexity joined covalently to a protein. They are usually found on the outer face of the plasma membrane (as part of the glycocalyx), in the extracellular matrix, and in the blood. Inside cells they are found in specific organelles such as Golgi complexes, secretory granules, and lysosomes. The oligosaccharide portions of glycoproteins are very heterogeneous and, like glycosaminoglycans, they are rich in information, forming highly specific sites for recognition and high affinity binding by carbohydrate-binding proteins called lectins. Some cytosolic and nuclear proteins can be glycosylated as well.
Glycosphingolipids are plasma membrane components in which the hydrophilic head groups are
oligosaccharides. As in glycoproteins, the oligosaccharides act as specific sites for recognition by lectins. The brain and neurons are rich in glycosphingolipids, which help in nerve conduction and myelin formation. Glycosphingolipids also play a role in signal transduction in cells.
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