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ESSENTIALS OF GLYCOBIOLOGY
LECTURE 14
DEGRADATION AND TURNOVER OF GLYCOCONJUGATES
Hud Freeze
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”.
SUGAR CHAIN DEGRADATION ENZYMES
Most Are:
Lysosome/Endosome
Low pH optimum,
Sugar/anomeric specificity
Exo-glycosidases
Targeted 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
Special Features for Degradation of
Different Glycoconjugates
TYPE
FEATURE
Glycoproteins
N-linked
O-linked
ER/Golgi/Cytoplasm/ Lysosome
Unexpected Products
Proteoglycans
Endoglycosidases
Unique ORDER
Non-glycohydrolase enzymes
Glycosphingolipids
Assisting proteins
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
lots of Man( )
Released
What happens to the released mannose?
OLIGOSACCHARIDE HOUSE-KEEPING CENTRAL
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
cytosol
Lysosome
Glycans
ER
Lysosomal degradation of N-linked oligosaccharides
Lysosomal degradation of N-linked oligosaccharides
Enzymatic defects are usually found by accumulation of
Partially degraded oligosaccharides in urine
O-LINKED OLIGOSACCHARIDE DEGRADATION
Same enzymes used for N-linked oligosaccharide degradation
a-GalNAc’ase deficiency--produce GalNAc terminated
Oligosaccharides?
a Ser/Thr
Excretion of GalNAc-a-Ser/Thr?
No!!
Why Not?
The oligosaccharides are larger size!
How to explain this?
a Ser/Thr
Partially degraded polysaccharides accumulate in tissues
and urine.
Structural analysis of glycans used to work out pathway
Hyaluronan degradation
HEPARAN SULFATE DEGRADATION
HEPARAN SULFATE DEGRADATION
CHONDROITIN SULFATE DEGRADATION
GSL Degradation
Needs Assistants
LIFE CYCLE OF GM2 ACTIVATOR PROTEIN
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.
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