Glycosaminoglycans and Glycoproteins. UNIT II: Intermediary Metabolism. Overview of glycosaminoglycans.
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Note: this is in comparison to the glycoproteins, which consist primarily of protein with a small amount of CHO
Note: a single exception is keratan sulfate, in which galactose rather than an acidic sugar is present
Figure 14.1. Repeating disaccharide unit.
Figure 14.2. Some monosaccharide units found in glycosaminoglycans.
Figure 14.3. Resilience of glycosaminoglycans.
- All of the GAGs, except hyaluronic cid, are found covalently attached to proteins, forming proteoglycan monomers.
1. Structure of proteoglycan monomer:
- A proteoglycan monomer found in cartilage consists of a core protein to which the linear GAG chains are covalently attached
Note: a number of proteoglycans have been characterized & named based on their structure & functional location. E.g., syndecan is an integral memb proteoglycan, versican & aggrecan are the predominant extracellular proteoglycans, & neurocan & cerebrocan are found primarily in the NS.
Figure 14.5. "Bottle-brush" model of a cartilage proteoglycan monomer.
Figure 14.7. Proteoglycan aggregate.
1. N-acetylglucosamine (gluNAc) & N-acetylgalactosamine (galNAc):
- The monosacch F-6-P is the precursor of gluNAc, galNAc, & the sialic acids, including N-acetylneuraminic acid (NANA, a nine-carbon, acidic monosacch).
Note: the amino groups are almost always acetylated
- The UDP-derivatives of gluNAc & galNAc are synthesized by reactions analogous to those described for UDP-glucose synthesis. These are activated forms of the monosaccharides that can be used to elongate the CHO chain
Note: before NANA can be added to a growing oligosacch, it must be converted into its active form by reacting with cytidine triphosphate (CTP). The enz N-acetylneuraminate-CMP-pyrophosphorylase removes pyrophosphate from CTP & attaches the remaining CMP to the NANA. This is the only nucleotide sugar in human metabolism in which the carrier nucleotide is a monophosphate
Figure 14.8. Synthesis of the amino sugars.
2. L-iduronic acid synthesis:
Figure 14.9. Uronic acid pathway.
Figure 14.10. Oxidation of UDP-glucose to UDP-glucuronic acid.
D. Synthesis of the carbohydrate chain
Figure 14.11. Synthesis of chondroitin sulfate.
Note: a defect in the sulfation process results in one of several autosomal recessive disorders that affect the proper development & maintenance of the skeletal system. This illustrates the importance of the sulfation step
B. Lysosomal degradation of GAGs
- The lysosomal degradation of GAGs requires a large # of acid hydrolases for complete digestion.
- 1st , the polysacch chains are cleaved by endoglycosidases, producing oligosaccharides. Further degradation of the oligosacch’s occurs sequentially from the non-reducing end of each chain, the last group (sulfate or sugar) added during synthesis being the 1st to be removed. Examples of some of these enz’s & the bonds they hydrolyze Fig 12.
Note: some of lysosomal enzymes required for degradation of GAGs also participate in degradation of glycolipids & glycoproteins. Therefore, an individual suffering from a specific mucopolysaccharidosis may also have a lipidosis or glycoprotein-oligosaccharidosis
Figure 14.12 cellular level of lysosomal hydrolases. Children who are homozygous for one of these diseases are apparently normal at birth, then gradually deteriorate. In severe cases, death occurs in childhood.
Degradation of the glycosaminoglycan heparan sulfate by lysosomal enzymes, indicating
sites of enzyme deficiencies in some representative mucopolysaccharidoses.
Hurler’s Syndrome cellular level of lysosomal hydrolases. Children who are homozygous for one of these diseases are apparently normal at birth, then gradually deteriorate. In severe cases, death occurs in childhood.(Mucopolysaccharidosis I)
VI. Overview of glycoproteins syndrome
Figure 14.13. syndrome Functions of glycoproteins.
A. Structure of the linkage between carbohydrate and protein
- The oligosacch may be attached to the protein through an N- or O-glycosidic link.
Note: in case of collagen, there is an O-glycosidic linkage b/w galactose or gluc & hydroxyl group of hydroxylysine
B. N- and O-linked oligosaccharides syndrome
- The N-linked oligosacch’s fall into 2 broad classes: complex oligosacch’s & high-mannose oligosacch’s. both contain same core pentasaccharide (Fig 14), but the complex oligosacch’s contain a diverse group of additional sugars, e.g., N-acetylglucosamine (GlcNAc), L-fucose (Fuc), N-acetylneuraminic acid (NANA), whereas the high-mannose oligosacch’s contain primarily mannose (Man)
Figure 14.14. syndrome Complex (top) and high-mannose (bottom) oligosaccharides.
VIII. Synthesis of glycoproteins syndrome
Figure 14.15 syndrome
Transport of glycoproteins through the Golgi apparatus and their subsequent release or
incorporation into a lysosome or the cell membrane.
Note: when NANA is present, the oligosacch has a –ve charge at physiologic pH.
B. Synthesis of O-linked glycosides syndrome
1. Role of glycosyltransferases
1. Synthesis of dolichol-linked oligosaccharide
2. Final processing of N-linked oligosaccharides:
Synthesis of N-linked glycoproteins. = N-acetylglucosamine; = mannose; = glucose;
= N-acetylgalactosamine; or for example, fucose or N-acetylneuraminic acid.
3. Enzymes destined for lysosomes: = mannose; = glucose;
Note: I-cell disease is so-named because of the large inclusion bodies seen in cells of patients with this disease
Figure 14.17. are Mechanism for transport of N-linked glycoproteins to the lysosomes.
Note: these disorders are very often directly associated with the same enzyme deficiencies involved in mucopolysaccharidoses & the inability to degrade glycolipids