Cell Surface Heparan Sulfate Proteoglycans O O OX CH 2 OX NHY O COOH O OH O Cells adapt structures of surface HS chains in response to their environment.

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Cell Surface Heparan Sulfate Proteoglycans O O OX CH 2 OX NHY O COOH O OH O 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) -P P- kinase Signalling pathways Growth factor receptor GF

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

Gal GlcAIdoA GlcNAc GalNAc 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)- Nascent Glycosaminoglycan Repeating Disaccharides Biosynthetic enzymes modify specific positions with sulfate, epimerize some GlcA to IdoA, and, in KS, may add monosaccharides (NeuAc, Fuc)

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

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 Examples of GAG hexamers: the possible modifications at the monosaccharide level are indicated.

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.