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Essentials of Glycobiology March 27th, 2008 Ajit Varki

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  1. Essentials of GlycobiologyMarch 27th, 2008Ajit Varki Lecture 1 Chap 1: Historical Background and Overview Chap 6: Biological Roles of Glycans (Chap 2: Saccharide Structure & Nomenclature)

  2. 1999

  3. 2008

  4. General Questions for Lecture 1 Why are studies of the biology of glycans ("glycobiology") not fully integrated into conventional molecular and cellular biology? Why has evolution repeatedly selected for glycans to be the dominant molecules on all cell surfaces? Why are extracellular and nuclear/cytosolic glycans so different from one another? What are the different ways in which glycans can mediate or modulate biological functions?

  5. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2


  6. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 (See also Table 1) MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 (See also Chapter 2) GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2

  7. ? ? DNA ORGANISM A DNA-Centric View of Biology DNA RNA PROTEIN CELL ORGANISM

  8. An “Holistic” View of Molecular & Cellular Biology ENZYMES REGULATORY FACTORS GLYCANS DIET LIPIDS SIGNALLING MOLECULES GLYCOPROTEINS PROTEOGLYCANS GLYCOLIPIDS MICROBES PARASITES CELL MATRIX PHYSICAL ENVIRONMENT CULTURAL ENVIRONMENT TISSUES & ORGANS ORGANISM DNA DNA RNA PROTEINS DNA

  9. FIGURE 1.4. Historical electron micrograph of endothelial cells from a blood capillary in the diaphragm muscle of a rat, showing the lumenal cell membrane of the cells (facing the blood) decorated with particles of cationized ferritin (arrowheads).

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

  11. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 (See also Table 1) MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 (See also Chapter 2) GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2

  12. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 (See also Table 1) MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 (See also Chapter 2) GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2

  13. 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

  14. 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”

  15. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 (See also Table 1) MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 (See also Chapter 2) GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2

  16. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 (See also Table 1) MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 (See also Chapter 2) GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2

  17. Macromolecules

  18. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 (See also Table 1) MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 (See also Chapter 2) GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2

  19. Essentials Second Edition Symbols See Figure 2.4 for the real structures

  20. Various Representations of an N-Glycan See Figure 2.19 for a Full Structure

  21. Symbolic Representation of Glycosaminoglycans

  22. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 (See also Table 1) MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 (See also Chapter 2) GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2

  23. Major Glycan Classes in Vertebrate Cells

  24. Types of Glycan-Protein Linkages in Nature

  25. 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.

  26. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 (See also Table 1) MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 (See also Chapter 2) GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2

  27. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 (See also Table 1) MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 (See also Chapter 2) GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2

  28. Life History of a Monosacharide

  29. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 (See also Table 1) MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 (See also Chapter 2) GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2

  30. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 (See also Table 1) MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 (See also Chapter 2) GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2

  31. Chapter 1: Historical Background and Overview WHAT IS GLYCOBIOLOGY?, 2 HISTORICAL ORIGINS OF GLYCOBIOLOGY, 3 (See also Table 1) MONOSACCHARIDES ARE THE BASIC STRUCTURAL UNITS OF GLYCANS, 3 (See also Chapter 2) GLYCANS CAN CONSTITUTE A MAJOR PORTION OF THE MASS OF A GLYCOCONJUGATE, 4 MONOSACCHARIDES CAN BE LINKED TOGETHER IN MANY MORE WAYS 11 COMMON MONOSACCHARIDE UNITS OF GLYCOCONJUGATES, 11 MAJOR CLASSES OF GLYCOCONJUGATES AND GLYCANS, 14 GLYCAN STRUCTURES ARE NOT ENCODED DIRECTLY IN THE GENOME, 16 SITE-SPECIFIC STRUCTURAL DIVERSITY IN PROTEIN GLYCOSYLATION, 16 CELL BIOLOGY OF GLYCOSYLATION, 17 TOOLS USED TO STUDY GLYCOSYLATION, 18 GLYCOMICS, 18 GLYCOSYLATION DEFECTS IN ORGANISMS AND CULTURED CELLS, 20 THE BIOLOGICAL ROLES OF GLYCANS ARE DIVERSE, 20 GLYCOSYLATION CHANGES IN DEVELOPMENT, DIFFERENTIATION, AND MALIGNANCY, 21 EVOLUTIONARY CONSIDERATIONS IN GLYCOBIOLOGY, 21 GLYCANS ARE IMPORTANT IN MEDICINE AND BIOTECHNOLOGY, 2

  32. Chapter 6: Biological Roles of Glycans GENERAL PRINCIPLES, 75 BIOLOGICAL CONSEQUENCES OF ALTERING GLYCOSYLATION ARE VARIABLE, 77 STRUCTURAL AND MODULATORY ROLES OF GLYCANS, 77 GLYCANS AS SPECIFIC LIGANDS FOR CELL–CELL INTERACTIONS (INTRINSIC RECOGNITION), 80 GLYCANS AS SPECIFIC LIGANDS FOR CELL–MICROBE INTERACTIONS (EXTRINSIC RECOGNITION), 81 MOLECULAR MIMICRY OF HOST GLYCANS BY PATHOGENS, 81 THE SAME GLYCAN CAN HAVE DIFFERENT ROLES WITHIN AN ORGANISM, 81 INTRASPECIES AND INTERSPECIES VARIATIONS IN GLYCOSYLATION, 82 IMPORTANCE OF TERMINAL SEQUENCES, MODIFICATIONS, AND UNUSUAL STRUCTURES, 82 ARE THERE “JUNK” GLYCANS?, 82 APPROACHES TO ELUCIDATING SPECIFIC BIOLOGICAL ROLES OF GLYCANS, 83

  33. Chapter 6: Biological Roles of Glycans GENERAL PRINCIPLES, 75 BIOLOGICAL CONSEQUENCES OF ALTERING GLYCOSYLATION ARE VARIABLE, 77 STRUCTURAL AND MODULATORY ROLES OF GLYCANS, 77 GLYCANS AS SPECIFIC LIGANDS FOR CELL–CELL INTERACTIONS (INTRINSIC RECOGNITION), 80 GLYCANS AS SPECIFIC LIGANDS FOR CELL–MICROBE INTERACTIONS (EXTRINSIC RECOGNITION), 81 MOLECULAR MIMICRY OF HOST GLYCANS BY PATHOGENS, 81 THE SAME GLYCAN CAN HAVE DIFFERENT ROLES WITHIN AN ORGANISM, 81 INTRASPECIES AND INTERSPECIES VARIATIONS IN GLYCOSYLATION, 82 IMPORTANCE OF TERMINAL SEQUENCES, MODIFICATIONS, AND UNUSUAL STRUCTURES, 82 ARE THERE “JUNK” GLYCANS?, 82 APPROACHES TO ELUCIDATING SPECIFIC BIOLOGICAL ROLES OF GLYCANS, 83

  34. Chapter 6: Biological Roles of Glycans GENERAL PRINCIPLES, 75 BIOLOGICAL CONSEQUENCES OF ALTERING GLYCOSYLATION ARE VARIABLE, 77 STRUCTURAL AND MODULATORY ROLES OF GLYCANS, 77 GLYCANS AS SPECIFIC LIGANDS FOR CELL–CELL INTERACTIONS (INTRINSIC RECOGNITION), 80 GLYCANS AS SPECIFIC LIGANDS FOR CELL–MICROBE INTERACTIONS (EXTRINSIC RECOGNITION), 81 MOLECULAR MIMICRY OF HOST GLYCANS BY PATHOGENS, 81 THE SAME GLYCAN CAN HAVE DIFFERENT ROLES WITHIN AN ORGANISM, 81 INTRASPECIES AND INTERSPECIES VARIATIONS IN GLYCOSYLATION, 82 IMPORTANCE OF TERMINAL SEQUENCES, MODIFICATIONS, AND UNUSUAL STRUCTURES, 82 ARE THERE “JUNK” GLYCANS?, 82 APPROACHES TO ELUCIDATING SPECIFIC BIOLOGICAL ROLES OF GLYCANS, 83

  35. Chapter 6: Biological Roles of Glycans GENERAL PRINCIPLES, 75 BIOLOGICAL CONSEQUENCES OF ALTERING GLYCOSYLATION ARE VARIABLE, 77 STRUCTURAL AND MODULATORY ROLES OF GLYCANS, 77 GLYCANS AS SPECIFIC LIGANDS FOR CELL–CELL INTERACTIONS (INTRINSIC RECOGNITION), 80 GLYCANS AS SPECIFIC LIGANDS FOR CELL–MICROBE INTERACTIONS (EXTRINSIC RECOGNITION), 81 MOLECULAR MIMICRY OF HOST GLYCANS BY PATHOGENS, 81 THE SAME GLYCAN CAN HAVE DIFFERENT ROLES WITHIN AN ORGANISM, 81 INTRASPECIES AND INTERSPECIES VARIATIONS IN GLYCOSYLATION, 82 IMPORTANCE OF TERMINAL SEQUENCES, MODIFICATIONS, AND UNUSUAL STRUCTURES, 82 ARE THERE “JUNK” GLYCANS?, 82 APPROACHES TO ELUCIDATING SPECIFIC BIOLOGICAL ROLES OF GLYCANS, 83

  36. Chapter 6: Biological Roles of Glycans GENERAL PRINCIPLES, 75 BIOLOGICAL CONSEQUENCES OF ALTERING GLYCOSYLATION ARE VARIABLE, 77 STRUCTURAL AND MODULATORY ROLES OF GLYCANS, 77 GLYCANS AS SPECIFIC LIGANDS FOR CELL–CELL INTERACTIONS (INTRINSIC RECOGNITION), 80 GLYCANS AS SPECIFIC LIGANDS FOR CELL–MICROBE INTERACTIONS (EXTRINSIC RECOGNITION), 81 MOLECULAR MIMICRY OF HOST GLYCANS BY PATHOGENS, 81 THE SAME GLYCAN CAN HAVE DIFFERENT ROLES WITHIN AN ORGANISM, 81 INTRASPECIES AND INTERSPECIES VARIATIONS IN GLYCOSYLATION, 82 IMPORTANCE OF TERMINAL SEQUENCES, MODIFICATIONS, AND UNUSUAL STRUCTURES, 82 ARE THERE “JUNK” GLYCANS?, 82 APPROACHES TO ELUCIDATING SPECIFIC BIOLOGICAL ROLES OF GLYCANS, 83

  37. Chapter 6: Biological Roles of Glycans GENERAL PRINCIPLES, 75 BIOLOGICAL CONSEQUENCES OF ALTERING GLYCOSYLATION ARE VARIABLE, 77 STRUCTURAL AND MODULATORY ROLES OF GLYCANS, 77 GLYCANS AS SPECIFIC LIGANDS FOR CELL–CELL INTERACTIONS (INTRINSIC RECOGNITION), 80 GLYCANS AS SPECIFIC LIGANDS FOR CELL–MICROBE INTERACTIONS (EXTRINSIC RECOGNITION), 81 MOLECULAR MIMICRY OF HOST GLYCANS BY PATHOGENS, 81 THE SAME GLYCAN CAN HAVE DIFFERENT ROLES WITHIN AN ORGANISM, 81 INTRASPECIES AND INTERSPECIES VARIATIONS IN GLYCOSYLATION, 82 IMPORTANCE OF TERMINAL SEQUENCES, MODIFICATIONS, AND UNUSUAL STRUCTURES, 82 ARE THERE “JUNK” GLYCANS?, 82 APPROACHES TO ELUCIDATING SPECIFIC BIOLOGICAL ROLES OF GLYCANS, 83

  38. Chapter 6: Biological Roles of Glycans GENERAL PRINCIPLES, 75 BIOLOGICAL CONSEQUENCES OF ALTERING GLYCOSYLATION ARE VARIABLE, 77 STRUCTURAL AND MODULATORY ROLES OF GLYCANS, 77 GLYCANS AS SPECIFIC LIGANDS FOR CELL–CELL INTERACTIONS (INTRINSIC RECOGNITION), 80 GLYCANS AS SPECIFIC LIGANDS FOR CELL–MICROBE INTERACTIONS (EXTRINSIC RECOGNITION), 81 MOLECULAR MIMICRY OF HOST GLYCANS BY PATHOGENS, 81 THE SAME GLYCAN CAN HAVE DIFFERENT ROLES WITHIN AN ORGANISM, 81 INTRASPECIES AND INTERSPECIES VARIATIONS IN GLYCOSYLATION, 82 IMPORTANCE OF TERMINAL SEQUENCES, MODIFICATIONS, AND UNUSUAL STRUCTURES, 82 ARE THERE “JUNK” GLYCANS?, 82 APPROACHES TO ELUCIDATING SPECIFIC BIOLOGICAL ROLES OF GLYCANS, 83

  39. Chapter 6: Biological Roles of Glycans GENERAL PRINCIPLES, 75 BIOLOGICAL CONSEQUENCES OF ALTERING GLYCOSYLATION ARE VARIABLE, 77 STRUCTURAL AND MODULATORY ROLES OF GLYCANS, 77 GLYCANS AS SPECIFIC LIGANDS FOR CELL–CELL INTERACTIONS (INTRINSIC RECOGNITION), 80 GLYCANS AS SPECIFIC LIGANDS FOR CELL–MICROBE INTERACTIONS (EXTRINSIC RECOGNITION), 81 MOLECULAR MIMICRY OF HOST GLYCANS BY PATHOGENS, 81 THE SAME GLYCAN CAN HAVE DIFFERENT ROLES WITHIN AN ORGANISM, 81 INTRASPECIES AND INTERSPECIES VARIATIONS IN GLYCOSYLATION, 82 IMPORTANCE OF TERMINAL SEQUENCES, MODIFICATIONS, AND UNUSUAL STRUCTURES, 82 ARE THERE “JUNK” GLYCANS?, 82 APPROACHES TO ELUCIDATING SPECIFIC BIOLOGICAL ROLES OF GLYCANS, 83

  40. Chapter 6: Biological Roles of Glycans GENERAL PRINCIPLES, 75 BIOLOGICAL CONSEQUENCES OF ALTERING GLYCOSYLATION ARE VARIABLE, 77 STRUCTURAL AND MODULATORY ROLES OF GLYCANS, 77 GLYCANS AS SPECIFIC LIGANDS FOR CELL–CELL INTERACTIONS (INTRINSIC RECOGNITION), 80 GLYCANS AS SPECIFIC LIGANDS FOR CELL–MICROBE INTERACTIONS (EXTRINSIC RECOGNITION), 81 MOLECULAR MIMICRY OF HOST GLYCANS BY PATHOGENS, 81 THE SAME GLYCAN CAN HAVE DIFFERENT ROLES WITHIN AN ORGANISM, 81 INTRASPECIES AND INTERSPECIES VARIATIONS IN GLYCOSYLATION, 82 IMPORTANCE OF TERMINAL SEQUENCES, MODIFICATIONS, AND UNUSUAL STRUCTURES, 82 ARE THERE “JUNK” GLYCANS?, 82 APPROACHES TO ELUCIDATING SPECIFIC BIOLOGICAL ROLES OF GLYCANS, 83 Localization of or Interference with Specific Glycans Using Glycan-binding Proteins or Antibodies, 83 Metabolic Inhibition or Alteration of Glycosylation, 84 Finding Natural Glycan Ligands for Specific Receptors, 85 Finding Receptors that Recognize Specific Glycans, 85 Interference by Soluble Glycans or Structural Mimics, 85 Eliminating Specific Glycan Structures by Glycosidases, 86 Studying Natural or Genetically Engineered Glycan Mutants, 86 Studying Natural or Genetically Engineered Glycan Receptor Mutants, 87

  41. General Questions for Lecture 1 Why are studies of the biology of glycans ("glycobiology") not fully integrated into conventional molecular and cellular biology? Why has evolution repeatedly selected for glycans to be the dominant molecules on all cell surfaces? Why are extracellular and nuclear/cytosolic glycans so different from one another? What are the different ways in which glycans can mediate or modulate biological functions?

  42. “Universal” Principles of Glycobiology Occurrence All cells in nature are covered with a dense and complex array of sugar chains (glycans). The cell walls of bacteria and archea are composed of several classes of glycans and glycoconjugates. Most secreted proteins of eukaryotes also carry large amounts of covalently attached glycans. In eukaryotes, these cell-surface and secreted glycans are mostly assembled via the ER-Golgi pathway. The extracellular matrix of eukaryotes is also rich in such secreted glycans. Cytosolic and nuclear glycans are common in eukaryotes. For topological, evolutionary, and biophysical reasons, there is little similarity between cell surface/secreted and nuclear/cytosolic glycans.

  43. “Universal” Principles of Glycobiology Chemistry and Structure Glycosidic linkages can be in - or - linkage forms, which are biologically recognized as completely distinct Glycan chains can be linear or branched Glycans can be modified by a variety of different substituents, such as acetylation and sulfation Complete sequencing of glycans is feasible, but usually requires combinatorial or iterative methods Modern methods allow in vitro chemoenzymatic synthesis of both simple and complex glycans