Glycosaminoglycans and Glycoproteins. UNIT II: Intermediary Metabolism. Overview of glycosaminoglycans.
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Glycosaminoglycans and Glycoproteins
Note: this is in comparison to the glycoproteins, which consist primarily of protein with a small amount of CHO
II. Structure of GAGs
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.
A. Relationship between GAG structure and function
Figure 14.3. Resilience of glycosaminoglycans.
C. Structure of proteoglycans
- 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.
2. Linkage between the carbohydrate chain & the protein
3. Proteoglycan aggregates
Figure 14.7. Proteoglycan aggregate.
III. Synthesis of glycosaminoglycans
A. Synthesis of amino sugars
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
2. N-Acetylneuraminic acid:
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.
B. Synthesis of acidic sugars
1. Glucuronic acid:
2. L-iduronic acid synthesis:
Figure 14.9. Uronic acid pathway.
Figure 14.10. Oxidation of UDP-glucose to UDP-glucuronic acid.
C. Synthesis of the core protein
D. Synthesis of the carbohydrate chain
Figure 14.11. Synthesis of chondroitin sulfate.
E. Addition of sulfate groups
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
IV. Degradation of glycosaminoglycans
A. Phagocytosis of extracellular glycosaminoglycans
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
Degradation of the glycosaminoglycan heparan sulfate by lysosomal enzymes, indicating
sites of enzyme deficiencies in some representative mucopolysaccharidoses.
Hurler’s Syndrome(Mucopolysaccharidosis I)
Facies of a male with the mucopolysaccharidosis, Hunter syndrome
VI. Overview of glycoproteins
Figure 14.13. Functions of glycoproteins.
VII. Structure of glycoprotein oligosaccharides
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
- 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. Complex (top) and high-mannose (bottom) oligosaccharides.
VIII. Synthesis of glycoproteins
Transport of glycoproteins through the Golgi apparatus and their subsequent release or
incorporation into a lysosome or the cell membrane.
A. Carbohydrate components of glycoproteins
Note: when NANA is present, the oligosacch has a –ve charge at physiologic pH.
B. Synthesis of O-linked glycosides
1. Role of glycosyltransferases
C. Synthesis of the N-linked glycosides
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:
Note: I-cell disease is so-named because of the large inclusion bodies seen in cells of patients with this disease
Figure 14.17. Mechanism for transport of N-linked glycoproteins to the lysosomes.
IX. Lysosomal degradation of glycoproteins
Note: these disorders are very often directly associated with the same enzyme deficiencies involved in mucopolysaccharidoses & the inability to degrade glycolipids