ESSENTIALS OF GLYCOBIOLOGY

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ESSENTIALS OF GLYCOBIOLOGY LECTURE
14 DEGRADATION AND TURNOVER OF GLYCOCONJUGATES Hu
d Freeze
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• USUAL TURNOVER
• Most glycans are extracellular or on cell surface
• Membrane recycling
• Receptor and non-receptor
• mediated endocytosis

To Endosome Lysosome
Lysosomal exoglycosidases degrade glycans at low
pH Specific 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/Endosome Low pH optimum,
Sugar/anomeric specificity Exo-glycosidases Targe
ted to lysosome through P-lectins and
Man-6-P But Some Are Non-lysosomal Active near
neutral pH Endoglycosidases Targeted as membrane
bound molecules Not in the lysosome
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Special Features for Degradation of Different
Glycoconjugates
TYPE FEATURE Glycoproteins N-linked ER/Golgi
/Cytoplasm/ Lysosome O-linked Unexpected
Products Proteoglycans Endoglycosidases Uniq
ue ORDER Non-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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MANNOSE METABOLISM IN CELLS AND MORE
Mannose in plasma comes from Oligosaccharide
turnover in cells
Cells also produce mannose From glucose Glc
Glc-6-P Fru-6-P Man-6-P
Golgi
Lysosome
cytosol
Glycans
ER
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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 a-GalNAcase deficiency--produce
GalNAc terminated Oligosaccharides? Excretion
of GalNAc-a-Ser/Thr? No!! Why Not? The
oligosaccharides are larger size! How to explain
this?
a
Ser/Thr
a
Ser/Thr
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Partially degraded polysaccharides accumulate in
tissues and 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 Degradation Needs 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