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Essentials of Glycobiology March 30th, 2004 Ajit Varki

Essentials of Glycobiology March 30th, 2004 Ajit Varki. Lecture 1 Course Overview & General Introduction. Online at NCBI http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books. Lecture 1 - Key Points. What is Glycobiology? Central Dogma Basic definitions

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Essentials of Glycobiology March 30th, 2004 Ajit Varki

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  1. Essentials of GlycobiologyMarch 30th, 2004Ajit Varki Lecture 1 Course Overview & General Introduction

  2. Online at NCBI http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books

  3. Lecture 1 - Key Points What is Glycobiology? Central Dogma Basic definitions Monosaccharides - the structural units of glycans Oligoaccharides consist of monosaccharides linked together Nomenclature and symbolic representations Major classes of glycoconjugates and oligosaccharides Clustered oligosaccharides Proteins can bind at either the ends of glycans or within the chains

  4. ? ? DNA ORGANISM DNA RNA PROTEIN CELL ORGANISM

  5. All Cells Are Coated with “Glycans” Electron micrograph of a human lymphocyte (Ruthenium Red staining)

  6. ENZYMES SUGARS TRANSCRIPTION FACTORS LIPIDS DIET SIGNALLING MOLECULES GLYCOPROTEINS PROTEOGLYCANS GLYCOLIPIDS ORGANISM MICROBES PARASITES CELL MATRIX PHYSICAL ENVIRONMENT TISSUES & ORGANS DNA RNA PROTEINS DNA DNA

  7. Macromolecules

  8. What is Glycobiology? Study of the structure, biosynthesis and biology of saccharides (sugar chains or “glycans”) in nature. Glycobiology is an integrative science, crossing all subfields of chemistry, biology and medicine. Chemical analysis and biochemistry dominated the field in the early part of the century. In the 1960’s, glycans in the extracellular matrix, on the cell surface, and in the interior of cells were found to have biological properties independent of the underlying protein or lipid. The term “Glycobiology” was coined in 1988 by Rademacher, Parekh, and Dwek: Annu Rev Biochem. 57:785-838.

  9. “Central Dogma” • Glycans occur in patterns that are characteristic of the cell-type, tissue and organism • Glycan patterning is not template driven • Instead, the glycan composition and pattern depends on expression of biosynthetic enzyme (transferases), substrate specificity, and the availability of precursors (i.e., more like “assembly-line driven)

  10. Lecture 1 - Key Points What is Glycobiology? Central Dogma Basic definitions Monosaccharides - the structural units of glycans Oligoaccharides consist of monosaccharides linked together Nomenclature and symbolic representations Major classes of glycoconjugates and oligosaccharides Clustered oligosaccharides Proteins can bind at either the ends of glycans or within the chains

  11. Basic Definitions • Monosaccharide: A carbohydrate that cannot be hydrolyzed into a simpler carbohydrate. The building block of oligosaccharides and polysaccharides. • Oligosaccharide: Linear or branched chain of monosaccharides attached to one another via glycosidic linkages. The number of monosaccharide units can vary. • Polysaccharide: Glycan composed of repeating monosaccharides, generally greater than ten monosaccharide units in length. • Carbohydrate, glycan, saccharide, sugar: Generic terms used interchangeably. Includes monosaccharides, oligosaccharides, polysaccharides, and derivatives of these compounds. Carbohydrates consist of “hydrated carbon”, [CH2O]n • Preferred generic term is “Glycan”

  12. Monosaccharides - the basic structural unit • Carbonyl group at the end of the carbon chain (aldoses) or at an inner carbon (ketoses) has potential reducing power. This end is called the reducing terminus, or reducing end • The ring form of a monosaccharide generates a chiral (anomeric) center (at C-1 for aldo sugars or at C-2 for keto sugars). Notice that other positions are chiral, which therefore imparts stereochemical information

  13. Oligosaccharides and Polysaccharides a-linkage b-linkage Glycosidic linkage can be a or b The convention is to draw the reducing end to the right and the non-reducing end to the left. Once in glycosidic linkage, ring can no longer open Reducing end is still called the same even when it is covelantly bound to another macromolecule (tying up its reducing power)

  14. Common Monosaccharides Neutral Sugars Amino Sugars Acidic Sugars

  15. Lecture 1 - Key Points What is Glycobiology? Central Dogma Basic definitions Monosaccharides - the structural units of glycans Oligoaccharides consist of monosaccharides linked together Nomenclature and symbolic representations Major classes of glycoconjugates and oligosaccharides Clustered oligosaccharides Proteins can bind at either the ends of glycans or within the chains

  16. Symbolic Representation of Common Monosaccharides • To simplify the structural complexity of glycans, we will generally use a standard set of symbols to represent sugars. • Symbol set is being modified for second edition of “Essentials”, in a consensus agreement with NCBI, Consortium for Functional Glycomics, KEGG and other national and international bodies

  17. Saccharide Modifications increase the diversity and functionality of glycans Ac = O-acetyl P = Phosphate S = O-Sulfate NS = N-Sulfate NH2 = free amino group

  18. Lecture 1 - Key Points What is Glycobiology? Central Dogma Basic definitions Monosaccharides - the structural units of glycans Oligoaccharides consist of monosaccharides linked together Nomenclature and symbolic representations Major classes of glycoconjugates and oligosaccharides Clustered oligosaccharides Proteins can bind at either the ends of glycans or within the chains

  19. Glycoconjugates • Glycoconjugate: A compound in which one or more glycans (the glycone) are covalently linked to a non-carbohydrate moiety (the aglycone). • Glycoproteins: A protein with one or more covalently bound glycans. • Glycolipids: A molecule containing a saccharide linked to a lipid. • Proteoglycans: Any glycoprotein with one or more covalently attached glycosaminoglycan chains. Schematic representation of the Thy-1 glycoprotein

  20. * *Several additional kinds of O-glycans have emerged recently Major Classes of Animal Glyconconjugates

  21. CHONDROITIN SULFATE HYALURONAN GLYCOSAMINO- GLYCANS HEPARAN SULFATE N-LINKED CHAINS O-LINKED CHAIN GLYCOPHOSPHO- LIPID ANCHOR GLYCOSPHINGOLIPID O-LINKED GlcNAc Major Glycan Classes in Animal Cells P S S S Ser-O- S S S S S -O-Ser NS NS Proteoglycan Ac P Etn S P N O N NH Asn Ser/Thr 2 Asn INOSITOL Glycoprotein Ac OUTSIDE P Sialic Acids INSIDE O Ser

  22. Symbolic Representation Full Traditional Simplified Traditional Symbolic Representation of Oligosaccharides

  23. Clustered O-linked Oligosaccharides • Electron micrograph of a cartilage proteoglycan shows the classical “bottle-brush” appearance • Many mucins contain clustered O-GalNAc linked oligosaccharides • These highly hydrated conjugates fill space, provide lubrication, and create clustered glycan ligands for binding receptors

  24. Lecture 1 - Key Points What is Glycobiology? Central Dogma Basic definitions Monosaccharides - the structural units of glycans Oligoaccharides consist of monosaccharides linked together Nomenclature and symbolic representations Major classes of glycoconjugates and oligosaccharides Clustered oligosaccharides Proteins can bind at either the ends of glycans or within the chains

  25. = Sialic acid Outer Chains Shared by Different Classes of Glycans can be recognized by Specific Proteins S N-LINKED CHAIN O N Ser/Thr Asn O-LINKED CHAIN Secreted Protein GLYCOSPHINGOLIPID S O N Membrane Protein Ser/Thr Asn OUTSIDE CELL MEMBRANE INSIDE

  26. Glycosaminoglycan Chains Contain Multiple Protein Binding Sites FGF-1 Antithrombin • Proteins can bind at the ends of N-linked and O-linked chains, and typically have shallow binding pockets • Other proteins bind to internal sugar sequences, and have binding clefts • Valency is a major factor in determining overall affinity

  27. Essentials of GlycobiologyMarch 30th, 2004Ajit Varki Lecture 1 Course Overview & General Introduction

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