7.3 Glycoconjugates: Proteoglycans, glycoproteins, and Glycolipids.
ESSENTIALS OF GLYCOBIOLOGY LECTURE 14 DEGRADATION AND TURNOVER OF GLYCOCONJUGATES Hud Freeze.
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Transcript of ESSENTIALS OF GLYCOBIOLOGY LECTURE 14 DEGRADATION AND TURNOVER OF GLYCOCONJUGATES Hud Freeze.
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ESSENTIALS OF GLYCOBIOLOGY
LECTURE 14DEGRADATION AND TURNOVER OF GLYCOCONJUGATES
Hud Freeze
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USUAL TURNOVER
• Most glycans are extracellular or on cell surface
• Membrane recycling
• Receptor and non-receptor mediated endocytosis
ToEndosomeLysosome
Lysosomal exoglycosidases degrade glycans at low pHSpecific lysosomal transporters carry neutral hexose, acetylatedaminohexose (GlcNAc, GalNAc), and Anionic sugars (GlcA, Sia) to the “cytosol”.
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SUGAR CHAIN DEGRADATION ENZYMES
Most Are:Lysosome/EndosomeLow pH optimum, Sugar/anomeric specificityExo-glycosidasesTargeted to lysosome through P-lectins and Man-6-P
But Some Are:Non-lysosomalActive near neutral pHEndoglycosidasesTargeted as membrane bound moleculesNot in the lysosome
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Special Features for Degradation of
Different Glycoconjugates
TYPE FEATURE
GlycoproteinsN-linked ER/Golgi/Cytoplasm/ LysosomeO-linked Unexpected Products
Proteoglycans EndoglycosidasesUnique ORDERNon-glycohydrolase enzymes
Glycosphingolipids Assisting proteins
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Special Problems for N-Linked Sugar Chains
• N-glycosylation occurs in ER-Topology for lysosomal degradation is wrong
• ~50% of ER proteins misfold and are degraded - what happens to the sugar chain? To glycopeptides?
• Protein synthetic rate and glycosylation rate must be coordinated
• Competition for lectin-based chaperones
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lots of Man( )Released
What happens to the released mannose?
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OLIGOSACCHARIDE HOUSE-KEEPING CENTRAL
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ER
Golgi
Lysosomecytosol
MANNOSE METABOLISM IN CELLS AND MORE
Cells also produce mannoseFrom glucoseGlc Glc-6-P Fru-6-P Man-6-P
Glycans
Mannose in plasma comes fromOligosaccharide turnover in cells
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Lysosomal degradation of N-linked oligosaccharides
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Lysosomal degradation of N-linked oligosaccharides
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Enzymatic defects are usually found by accumulation of Partially degraded oligosaccharides in urine
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O-LINKED OLIGOSACCHARIDE DEGRADATION
Same enzymes used for N-linked oligosaccharide degradation
-GalNAc’ase deficiency--produce GalNAc terminatedOligosaccharides?
Excretion of GalNAcSer/Thr?
No!!Why Not?
The oligosaccharides are larger size!
How to explain this?
Ser/Thr
Ser/Thr
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Partially degraded polysaccharides accumulate in tissuesand urine.Structural analysis of glycans used to work out pathway
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Hyaluronan degradation
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HEPARAN SULFATE DEGRADATION
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HEPARAN SULFATE DEGRADATION
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CHONDROITIN SULFATE DEGRADATION
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GSL DegradationNeeds Assistants
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LIFE CYCLE OF GM2 ACTIVATOR PROTEIN
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Model for the degradation of membrane-bound GlcCer by glucocerebrosidase and SAP-C and Cer by acid ceramidase and SAP-D, respectively. Besides the interaction of lysosomal enzyme and activator protein, the model emphasizes binding of activator protein and lysosomal enzymes to the vesicular surface containing BMP.
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REMEMBER THAT
•Different types of glycans have unique degradation pathways•Mutations in different degradative enzymes lead to rare diseases •Limiting glycan synthesis in genetic disorders reduces pathology•Tissue specific differences in salvage/de novo biosynthesis may
be important for health and lead to pathology