Degradation of Glycosaminoglycans

DEGRADATION OF GLYCOSAMINOGLYCANS

GAGs are degraded in lysosomes, which contain hydrolytic enzymes that are most active at a pH of approximately 5. Therefore, as a group, these enzymes are called acid hydrolases. [Note: The low pH optimum is a protective mechanism that prevents the enzymes from destroying the cell should leakage occur into the cytosol where the pH is neutral.] The half-lives of GAGs vary from minutes to months and are influenced by the type of GAG and its location in the body.

A. Phagocytosis of extracellular glycosaminoglycans

Because GAGs are extracellular or cell-surface compounds, they must first be engulfed by an invagination of the cell membrane (phagocytosis), forming a vesicle inside of which the GAGs are to be degraded. This vesicle then fuses with a lysosome, forming a single digestive vesicle in which the GAGs are efficiently degraded (see: for a discussion of phagocytosis).

B. Lysosomal degradation of glycosaminoglycans

The lysosomal degradation of GAGs requires a large number of acid hydrolases for complete digestion. First, the polysaccharide chains are cleaved by endoglycosidases, producing oligosaccharides. Further degradation of the oligosaccharides occurs sequentially from the nonreducing end of each chain, the last group (sulfate or sugar) added during synthesis being the first group removed (by sulfatases or exoglycosidases). Examples of some of these enzymes and the bonds they hydrolyze are shown in Figure 14.12. [Note: Endo- and exoglycosidases are also involved in the lysosomal degradation of glycoproteins and glycolipids. Deficiencies in these enzymes result in the accumulation of partially degraded carbohydrates, resulting in tissue damage.]

Multiple sulfatase deficiency is a rare lysosomal storage disease in which all sulfatases are nonfunctional due to a defect in the formation of formylglycine, an amino acid derivative required at the active site for enzymic activity to occur.

Figure 14.12 Degradation of the glycosaminoglycan heparan sulfate by lysosomal enzymes, indicating sites of enzyme deficiencies in some representative mucopolysaccharidoses (MPSs). [Note: Deficiencies in the degradation of keratan sulfate result in Morquio syndrome, A and B. Deficiencies in the degradation of dermatan sulfate result in Maroteaux-Lamy syndrome.] GlcUA = glucuronic acid; IdUA = iduronic acid; GalNAc = N-acetylgalactosamine; GlcNAc = N-acetylglucosamine; GlcN = glucosamine; S = sulfate.