essentials of glycobiology lecture 14 degradation and turnover of glycoconjugates hud freeze
TRANSCRIPT
ESSENTIALS OF GLYCOBIOLOGY
LECTURE 14DEGRADATION AND TURNOVER OF GLYCOCONJUGATES
Hud Freeze
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”.
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
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
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
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
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
-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
Partially degraded polysaccharides accumulate in tissuesand urine.Structural analysis of glycans used to work out pathway
Hyaluronan degradation
HEPARAN SULFATE DEGRADATION
HEPARAN SULFATE DEGRADATION
CHONDROITIN SULFATE DEGRADATION
GSL DegradationNeeds 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