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Glycosciences: Glycobiology & Glycochemistry e-learning course What sort of Science is Glycoscience? (Introductory lecture) Paula Videira Faculdade de Ciências Médicas Nova University, Lisbon Portugal Glycosciences: Glycobiology & Glycochemistry Glycoscience is the study of structure and function of carbohydrates — biological sugars Glycobiology and Glycochemistry are two main subareas Glycosciences: Glycobiology & Glycochemistry More complex deffinition for Glycosciences • The study of the structure, biosynthesis, biology, and evolution of saccharides (sugar chains or glycans) that are widely distributed in nature, and the proteins that recognize them. • The branch of science concerned with the role of sugars in biological systems. Glycosciences: Glycobiology & Glycochemistry DNA RNA PROTEINS ENZYMES REGULATORY FACTORS GLYCANS SIGNALLING MOLECULES LIPIDS GLYCOLIPIDS MICROBES PARASITES PHYSICAL ENVIRONMENT CELL GLYCOPROTEINS PROTEOGLYCANS MATRIX TISSUES & ORGANS DNA ORGANISM DNA DIET Glycans cover the surface of all eukaryotic cells, all prokaryotic cells and many viruses Glycan: A generic term for any sugar or assembly of sugars, in free form or attached to another molecule = +/- saccharide or carbohydrate GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE glycosylphosphatidylinositol Schematic representation of the Thy-1 glycoprotein Glycoconjugate: A molecule in which one or more glycan units are covalently linked to a noncarbohydrate entity Glycosciences: Glycobiology & Glycochemistry SURFACE GLYCOSYLATION IS UNIVERSAL IN LIVING ORGANISMS • Every free-living cell and every cell within multi-cellular organisms are covered with dense & complex layer of glycans. • Even enveloped viruses that bud from surfaces of infected cells carry with them the glycosylation patterns of the host cell. • Most secreted molecules are glycosylated, and extracellular matrices of multicellular organisms are rich in glycans • Biofilms/ matrices secreted by unicellular organisms also contain glycans. • Reasons for apparent universality of cell-surface and secreted glycosylation not clear. • Apparently, evolution selected for glycans as being the most diverse and flexible molecules for the interface between cells and the extracellular milieu. Glycosciences: Glycobiology & Glycochemistry Basic concepts • Glycan: generic term for any sugar or assembly of sugars (free form or attached to another molecule). May be used interchangeably with saccharide or carbohydrate. • Glycoconjugate: A molecule in which one or more glycan units are covalently linked to a noncarbohydrate entity (protein or lipid). • Carbohydrate: more generic term which includes monosaccharides, oligosaccharides, and polysaccharides as well as derivatives of these compounds Basic glycobiology concepts Common monosaccharides found in vertebrates Basic glycobiology concepts Symbol nomenclature for structural depictions Monosaccharide symbol set c b STANDARD SYMBOLS FOR GLYCAN STRUCTURES N-Linked α6 β4 β2 O-Linked α6 β4 β4 α3 α6 β4 α3 α6 β4 α3 β2 β6 β3 Fucα α1 NeuAcα α2-6Galβ β1-4GlcNAc β1-2Manα α1 NeuAc α 2-3Gal β 1-4GlcNAc β 1 6 6 Manβ β1-4GlcNAc β1-4GlcNac- Asn 3 6 GalNAc α -Thr 3 NeuAcα α2-6Galβ β1-4GlcNAc β1-2Manα α1 NeuAc α 2-3Gal β 1 Key: NeuAc Gal Glc Man Fuc GalNAc GlcNAc General pathways for biosynthesis Common classes of animal glycans phosphoethanolamine phosphatidylinositol General pathways for biosynthesis Initiation and maturation of the major types of eukaryotic glycoconjugates in relation to subcellular trafficking in the ER-Golgi– plasma membrane pathway General pathways for biosynthesis Vaccination with Theratope® (STn-KLH) as treatment for breast cancer Leona A Holmberg, Brenda M Sandmaier < Sialyl-Tn is a carbohydrate associated with MUC1. It is a unique tumor-associated antigen, present on many adenocarcinomas including breast, ovarian, colorectal, gastric and pancreatic. Consequently, SialylTN is an ideal candidate for boosting the patient’s immune system specifically against a unique tumorassociated antigen. The cancer vaccine Theratope® was developed by Biomira, Inc. using a synthetic Sialyl-Tn antigen that emulates the unique carbohydrate on human cancer. Clinical trials have predominately been carried out in breast cancer patients and these trials are outlined in this profile. The A, B, and H blood group antigens are glycans presented on the type-1 or type-2 Nacetyllactosamines, on O-GalNAc glycans (type-3), or on glycolipids (type-4). Glycosciences: Biosynthesis Glycobiology and heterogeneity & Glycochemistry GENERAL PRINCIPLES how do we get the sugars? • Glucose and fructose are major carbon and energy sources for most organisms as yeast and humans. • Most organisms can derive monosaccharides needed for glycan biosynthesis from these sources. • Not all of these biosynthetic pathways are equally active in all types of cells. Biosynthesis and heterogeneity Generalized Glycosyltransferase Reaction Nucleotide-Sugar + HO-Acceptor Glycosyltransferase Nucleotide Sugar-O-Acceptor (Product) Glycosciences: Biosynthesis Glycobiology and heterogeneity & Glycochemistry Most glycosylation reactions use activated sugar donors Biosynthesis and heterogeneity Biosynthesis and interconversion of monosaccharides Biosynthesis and e-learning heterogeneity Glycosciences: Glycobiology & Glycochemistry course Glycosylation Reactions Biosynthesis and heterogeneity Glycosyltransferases Glycosyltransferase Donor # Genes Family Substrates (min) FucosylSialylGalactosylN-AcetylglucosaminylN-AcetylgalactosaminylMannosylGlucosyl- GDP-Fucose CMP-NeuAc UDP-Gal UDP-GlcNAc UDP-GalNAc GDP-Man UDP-Glc 11 20 19 34 30 13 8 The Big Picture Biosynthesis Transferases & Hydrolases 잠; Glycan Glycan-Binding Proteins (Lectins) Function Thank you! 잠;