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Cell Surface Heparan Sulfate Proteoglycans

COOH. CH 2 OX. O. O. O. OX. OH. O. O. OX. NHY. GF. GF. Growth factor receptor. -P. P-. kinase. Signalling pathways. Cell Surface Heparan Sulfate Proteoglycans. Cells adapt structures of surface HS chains in response to their environment. A rapid method for sequencing HS

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Cell Surface Heparan Sulfate Proteoglycans

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  1. COOH CH2OX O O O OX OH O O OX NHY GF GF Growth factor receptor -P P- kinase Signalling pathways Cell Surface Heparan Sulfate Proteoglycans Cells adapt structures of surface HS chains in response to their environment. A rapid method for sequencing HS released from proteoglycans necessary: interactions with (FGFs, TGF, HB-EGF, VEGF)

  2. GlcA GlcNAc NA domain NS domain GlcNS6S IdoA2S • Instrumental sequencing of GAGs is required • What is the glycosaminoglycan phenotype at the molecular level?

  3. Nascent Glycosaminoglycan Repeating Disaccharides Heparin/Heparan sulfate: -GlcA(1-4)GlcNAc(1-4)- Chondroitin sulfate: -GlcA (1-3) -GalNAc (1-4)- Keratan Sulfate: -Gal (1-4)GlcNAc (1-3)- Hyaluronan (unsulfated): -GlcA(1-3)GlcNAc (1-4)- Biosynthetic enzymes modify specific positions with sulfate, epimerize some GlcA to IdoA, and, in KS, may add monosaccharides (NeuAc, Fuc) GlcNAc GlcA IdoA Gal GalNAc

  4. Biosynthesis of heparan sulfate GlcNAc transferase II GlcA transferase II Polymerization N-deacetylase/N-sulfotransferase Epimerization GlcA C5 epimerase 1. 2-O-sulfotransferase 2. 6-O-sulfotransferase 3. 3-O-sulfotransferase Sulfation GlcA GlcNAc GlcNS6S IdoA2S

  5. Examples of GAG hexamers: the possible modifications at the monosaccharide level are indicated. • Chondroitin sulfate (CS) • UroA(1-3)GalNAc(1-4) • GlcA/IdoA, IdoA2S, GaNAc4S, GalNAc6S, GalNAc4S6S • Heparan sulfate (HS) • UroA(1-4)GlcNAc(1-4) • GlcA/IdoA, IdoA2S, GlcNS, GlcNS6S, GlcNS3S6S • Keratan sulfate (KS) • Gal(1-4)GlcNAc(1-3) • Gal6S, GlcNAc6S, sialylation, fucosylation

  6. Why is GAG structure an important topic for research? • The mass spectrometric fragmentation characteristics of these highly sulfated molecules tells us a great deal about carbohydrates in general • The analysis of such fragile molecules is necessary for biochemistry/medicine to advance • Hidden biology: the functions chemical structures too fragile to analyze have been hidden to us (O-GlcNAc, sulfated CHOs, phospho-His) • GAGs are found on the surfaces of all adherent cells and mediate cell-cell and cell-matrix interactions, and as such are essential to higher eukaryotic development and play roles in diseases.

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