Chapter Summary, Questions Answers - Glycosaminoglycans, Proteoglycans, and Glycoproteins

CHAPTER SUMMARY

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. GAGs 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 GAGs, which led to the original naming of these compounds as mucopolysaccharides. There are six major types of GAGs, including chondroitin 4- and 6-sulfates, keratan sulfate, dermatan sulfate, heparin, heparan sulfate, and hyaluronic acid. All of the GAGs, except hyaluronic acid, are found covalently attached to protein, forming proteoglycan monomers, which consist of a core protein to which the linear GAG chains are covalently attached. The proteoglycan monomers associate with a molecule of hyaluronic acid to form proteoglycan aggregates. GAGs are synthesized in the Golgi. The polysaccharide chains are elongated by the sequential addition of alternating acidic and amino sugars, donated by their UDP-derivatives. D-glucuronate may be epimerized to L-iduronate. The last step in synthesis is sulfation of some of the amino sugars. The source of the sulfate is 3′-phosphoadenosyl-5′-phosphosulfate. The completed proteoglycans are secreted into the extracellular matrix or remain associated with the outer surface of cells. GAGs are degraded by lysosomal acid hydrolases. They are first broken down to oligosaccharides, which are degraded sequentially from the nonreducing end of each chain. A deficiency of any one of the hydrolases results in a mucopolysaccharidosis. These are hereditary disorders in which GAGs accumulate in tissues, causing symptoms such as skeletal and extracellular matrix deformities and intellectual disability. Examples of these genetic diseases include Hunter and Hurler syndromes. 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 antigenicity (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. Glycoproteins are synthesized in the rough endoplasmic reticulum (RER) and t h e Golgi. The precursors of the carbohydrate components of glycoproteins are nucleotide sugars. O-linked glycoproteins are synthesized in the Golgi by the sequential transfer of sugars from their nucleotide carriers to the hydroxyl group of a serine or threonine residue in the protein. N-linked glycoproteins contain varying amounts of mannose. They are synthesized by the transfer of a preformed oligosaccharide from its ER membrane lipid carrier, dolichol pyrophosphate, to the amide N of an asparagine residue in the protein. A deficiency in the phosphorylation of mannose residues in N-linked glycoprotein enzymes destined for the lysosomes results in I-cell disease. Glycoproteins are degraded in lysosomes by acid hydrolases. A deficiency of any one of these enzymes results in a lysosomal glycoprotein storage disease (oligosaccharidosis), resulting in accumulation of partially degraded structures in the lysosome.

Figure 14.18 Key concept map for glycosaminoglycans and glycoproteins. ECM = extracellular matrix.

Study Questions

Choose the ONE best answer.

14.1 Mucopolysaccharidoses are hereditary lysosomal storage diseases. They are caused by:

A. defects in the degradation of glycosaminoglycans.

B. defects in the targeting of enzymes to lysosomes.

C. an increased rate of synthesis of the carbohydrate component of proteoglycans.

D. an insufficient rate of synthesis of proteolytic enzymes.

E. the synthesis of abnormally small amounts of core proteins.

F. the synthesis of heteropolysaccharides with an altered structure.

Correct answer = A. The mucopolysaccharidoses are caused by deficiencies in any one of the lysosomal acid hydrolases responsible for the degradation of glycosaminoglycans (not proteins). The enzyme is correctly targeted to the lysosome, so blood levels of the enzyme do not increase, but it is nonfunctional. In these diseases, synthesis of the protein and carbohydrate components of proteoglycans is unaffected, both in terms of structure and amount.

14.2 The presence of the following compound in the urine of a patient suggests a deficiency in which one of the enzymes listed below?

A. Galactosidase

B. Glucuronidase

C. Iduronidase

D. Mannosidase

E. Sulfatase

Correct answer = E. Degradation of glycoproteins follows the rule “last on, first off.” Because sulfation is the last step in the synthesis of this sequence, a sulfatase is required for the next step in the degradation of the compound shown.

14.3 An 8-month-old boy with coarse facial features, skeletal abnormalities, and delays in both growth and development is diagnosed with I-cell disease based on his presentation and on histologic and biochemical testing. I-cell disease is characterized by:

A. decreased production of cell-surface O-linked glycoproteins.

B. elevated levels of acid hydrolases in the blood.

C. an inability to N-glycosylate proteins.

D. increased synthesis of proteoglycans.

E. oligosaccharides in the urine.

Correct answer = B. I-cell disease is a lysosomal storage disease caused by deficiency of a protein essential for synthesis of the mannose 6-phosphate signal that targets acid hydrolases to the lysosome. This results in secretion of these enzymes from the cell and accumulation of materials within the lysosome due to impaired degradation. None of the other choices relate in any way to I-cell disease or lysosomal function. Oligosaccharides in the urine are characteristic of the muco-and polysaccharidoses but not I-cell disease (a mucolipidosis).

14.4 An infant with corneal clouding has dermatan sulfate and heparin sulfate in his urine. Decreased activity of which of the enzymes listed below would confirm the suspected diagnosis of Hurler syndrome?

A. α-L-Iduronidase

B. β-Glucuronidase

C. Glycosyltransferase

D. Iduronate sulfatase

Correct answer = A. Hurler syndrome, a defect in the lysosomal degradation of glycosaminoglycans (GAGs) with corneal clouding, is due to a deficiency in α-L-iduronidase. β-glucuronidase is deficient in Sly syndrome, and iduronate sulfatase is deficient in Hunter syndrome. Glycosyltransferases are enzymes of GAG synthesis.

14.5 Distinguish between glycoproteins and proteoglycans.

Glycoproteins are proteins to which short, branched, oligosaccharide chains are attached. Proteoglycans consist of a core protein to which long, unbranched, glycosaminoglycan (GAG) chains are attached. GAGs are large complexes of negatively charged heteropolysaccharides composed of repeating [acidic sugar–amino sugar]n disaccharide units.