Glycoproteins and Mucins. B.Sopko
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1 Glycoproteins and Mucins B.Sopko
2 Content Glycoproteins: Structures and Linkages Interconversions and activation of dietary sugars Other pathways of sugar nucleotide metabolism Biosynthesis of oligosaccharides Functions of the oligosaccharide chains of glycoproteins Mucins Pathological glycosylation
3 Glycoproteins: Structures and Linkages Glycoproteins and Proteoglycans Glycoproteins Proteoglycans Protein >> carbohydrate Proteins conjugated to saccharides lacking a serial repeat unit Carbohydrate >> protein Repeat unit HexN and HexUA Glycosaminoglycans and Mucopolysaccharides
4 Glycoproteins: Structures and Linkages Structures of the oligosaccharides attached to proteins
5 Glycoproteins: Structures and Linkages Structures of the oligosaccharides attached to proteins
6 Interconversions and activation of dietary sugars
7 Fructose metabolism
8 UDP-glucose
9 GDP-mannose
10 Synthesis of amino-sugars and sialic acids
11 Interconversions and activation of dietary sugars - overview
12 Biosynthesis of oligosaccharides N-linked glycoproteins
13 N-linked glycoproteins
14 Serine O-linked glycoproteins
15 Route from the Golgi complex to the final destination
16 Functions of the oligosaccharide chains of glycoproteins N-linked oligosaccharides have an important role in protein folding High-mannose oligosaccharides target some proteins to specific sites in the cell The oligosaccharide chains of glycoproteins increase the solubility and stability of proteins Both N- and O-linked glycan structures are involved in recognition processes
17 High-mannose oligosaccharides target some proteins to specific sites in the cell
18 N-linked oligosaccharides have an important role in protein folding
19 The oligosaccharide chains of glycoproteins increase the solubility and stability of proteins
20 Both N- and O-linked glycan structures are involved in recognition processes
21 Lectins Lectins are defined as proteins that do not have enzymatic activity but that reversibly bind monosaccharides and oligosaccharides with high specificity.
22 Mucins - characterization Complex glycoproteins synthetized in epithelial cells Components of mucus secretions covering epithelial cells in gastrointestinal, urogenital, tracheobronchial, ocular and auditory systems of all vertebrates (but they can be found in all eukaryotes) Very rich in carbohydrates (50-90% of mucin mass is composed by sugars) and saccharides are linked to protein via O-glycosidic bond O-glycans are linked to serine/threonine in specific domain called tandem repeat Some mucins can also contain N-glycosidic oligosaccharides, but they are bound only in cysteine-rich domain Marked MUC1.
23 Mucins - structure
24 Mucins - types Membrane-tethered with TR (membrane mucins) e.g. MUC1, MUC4 Secreted, cysteine-poor with TR (gel forming cystein-poor mucins) - e.g. MUC7 Secreted, cysteine-rich with TR - MUC2, MUC5AC Mucins without TR
25 Mucins synthesis
26 Secreted mucins in the airways mucus gel and their sites of synthesis.
27 Secreted mucins in the airways mucus gel and their structure
28 Pathological glycosylation and glycation
29 I-CELL DISEASE I-cell disease results from an enzyme deficiency so that lysosomal enzymes do not aquire the targeting signal, mannose 6-phosphate. Fibroblasts in this disease have dense inclusion bodies (I-cells) and are deficient in many lysosomal enzymes. The lysosomes become engorged with indigestible substrates, leading to death in infancy.
30 N-linked oligosaccharides have an important role in protein folding
31 Carbohydratedeficient glycoprotein syndromes (CDGSs)
32 Carbohydrate-deficient glycoprotein syndromes (CDGSs) Disease Enzyme Deficiency Symptoms/Comments Aspartylglucosaminuria β-mannosidosis α-mannosidosis G M1 Gangliosidosis Sandhoff disease Sialidosis (also identified as Mucolipidosis I) aspartylglucosaminidase (N-aspartyl-β-glucosaminidase) β-mannosidase α-mannosidase β-galactosidase β-hexosaminidases A and B neuraminidase (sialidase) progressive mental retardation, delayed speech and motor development, coarse facial features primarily neurological defects, speech impairment mental retardation, dystosis multiplex, hepatosplenomegaly, hearing loss, delayed speech also identified as a glycosphingolipid storage disease or lysosomal storage disease also identified as a glycosphingolipid storage disease or lysosomal storage disease myoclonus, congenital ascites, hepatosplenomegaly, coarse facial features, delayed mental and motor development Fucosidosis α-fucosidase progressive motor and mental deterioration, growth retardation, coarse facial features, recurrent sinus and pulmonary infections
33 Decreased Cl - concentration results in thicker and less fluid mucous secretion Cystic fibrosis
34 Glycation (spontaneus glycosylation)
35 Glycation (spontaneus glycosylation) Extracellular proteins Intracellular proteins Long-lived proteins Collagen Type I, III and IV, cartilage, elastin, myelin, proteoglycan Lens crystallins, Neurofilaments Short-lived proteins Plasma proteins such as Apo B, LDL, albumin, immunoglobulins Hemoglobin, enzymes, lysosomes, ribonuclease and several membrane proteins
36 Glycation (spontaneus glycosylation)
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