What sort of Science is Glycoscience? (Introductory lecture)

Transcription

1 Glycosciences: Glycobiology & Glycochemistry e-learning course What sort of Science is Glycoscience? (Introductory lecture) Paula Videira Faculdade de Ciências Médicas Nova University, Lisbon Portugal

2 Glycosciences: Glycobiology & Glycochemistry Glycoscience is the study of structure and function of carbohydrates biological sugars Glycobiology and Glycochemistry are two main subareas

3 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.

4 Glycosciences: Glycobiology & Glycochemistry DNA RNA PROTEINS ENZYMES REGULATORY FACTORS GLYCANS DIET SIGNALLING MOLECULES LIPIDS GLYCOLIPIDS GLYCOPROTEINS PROTEOGLYCANS MICROBES PARASITES CELL MATRIX PHYSICAL ENVIRONMENT TISSUES & ORGANS ORGANISM DNA DNA

5 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

6 GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE Schematic representation of the Thy-1 glycoprotein glycosylphosphatidylinositol Glycoconjugate: A molecule in which one or more glycan units are covalently linked to a noncarbohydrate entity

7 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.

8 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

9 Common monosaccharides found in vertebrates Basic glycobiology concepts

10 Monosaccharide symbol set b Basic glycobiology concepts Symbol nomenclature for structural depictions c

11 STANDARD SYMBOLS FOR GLYCAN STRUCTURES N-Linked O-Linked α6 β4 β2 α6 β4 β4 α6 α3 β4 β6 α6 β4 β2 α3 α3 β3 NeuAcα2-6Galβ1-4GlcNAc β1-2manα1 NeuAcα2-6Galβ1-4GlcNAc β1-2manα1 Fucα1 6 6 Manβ1-4GlcNAc β1-4glcnac- Asn 3 NeuAc α2-3gal β1-4glcnac β1 NeuAc α2-3gal β1 6 GalNAc α-thr 3 Key: NeuAc Gal Glc Man Fuc GalNAc GlcNAc

12 General pathways for biosynthesis Common classes of animal glycans phosphoethanolamine phosphatidylinositol

13 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

14 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, Sialyl- TN 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.

15 The A, B, and H blood group antigens are glycans presented on the type-1 or type-2 N- acetyllactosamines, on O-GalNAc glycans (type-3), or on glycolipids (type-4).

16 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.

17 Biosynthesis and heterogeneity Generalized Glycosyltransferase Reaction Nucleotide-Sugar + HO-Acceptor Nucleotide Glycosyltransferase Sugar-O-Acceptor (Product)

18 Glycosciences: Biosynthesis Glycobiology and heterogeneity & Glycochemistry Most glycosylation reactions use activated sugar donors

19 Biosynthesis and heterogeneity Biosynthesis and interconversion of monosaccharides

20 Glycosciences: Glycobiology & Glycochemistry Biosynthesis and e-learning heterogeneity course Glycosylation Reactions

21 Glycosyltransferases Biosynthesis and heterogeneity Glycosyltransferase Family Donor Substrates # Genes (min) Fucosyl- GDP-Fucose 11 Sialyl- CMP-NeuAc 20 Galactosyl- UDP-Gal 19 N-Acetylglucosaminyl- UDP-GlcNAc 34 N-Acetylgalactosaminyl- UDP-GalNAc 30 Mannosyl- GDP-Man 13 Glucosyl- UDP-Glc 8

22 The Big Picture Biosynthesis Transferases & Hydrolases Glycan 잠 ; Glycan-Binding Proteins (Lectins) Function

23 Thank you! 잠 ;