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Glycan Structure Complexity

Date post: 02-Oct-2015
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Notes on structure of glycans
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Glycan structure and complexity
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  • Glycan structure and complexity

    'an' stands for polysaccharide (sugar), its nomenclature

  • Does genome size correlate with complexity of an organism?Organism Est size

    (bp)Est gene #

    Mean gene density Chromosome #

    human 3.2 x 109 ~ 25 K 1 gene

    per 100 K bases

    46

    mouse 2.6 x 109 ~ 25 K 1 gene

    per 100 K bases

    40

    Fruit fly 137 x 106 13 K 1 gene

    per 9 K bases

    8

    Round

    worm

    97 x 106 19 K 1 gene

    per 5 K bases

    12

    yeast 12 x 106 6 K 1 gene

    per 2 K bases

    32

    http://www.ornl.gov/sci/

    Genome size does not correlate with complexity of the organism. The number of genes is not proportionate with genome size.

  • Genomics Genes, deoxyribonucleic acid (DNA) sequence at the organismal level

    Intra-organismal cell-specific variations

    Proteomics Proteins and peptides, at levels of the organism, the tissue, or the cell

    Post-translational modifications

    Glycomics Glycans, at levels of the organism, the tissue, or the cell

    It is dynamicState 1 State 2

    Embryonic stem cell Differentiated cellNormal cell Cancer cellHealthy cell Injured cell

    study of genes

    Starch and glycogen not too complex, they're all made of glucose

    Cellulose made from N-acetyl galactosamine

    different monosaccharide increase complexity

    embryonic stem cell have different structure from differentiated

  • Where in the cell are glycans and glycoconjugates localized ?

    What are their functions at these localities?

    What properties are required for these functions?

    What molecular features support these properties?

    cell surface recognition mechanisms need glycogen present on cell surface (peri or extra cellular signal)

  • Glycolipids

    Glycoproteins

    Glycans are exposed to the extracellular environment

    extra, intra and transmembrane domain

    hexagon to represent glucose (hexose)----can be attached to phospholipids

  • Lectin-saccharideinteractions

    Kd = 10-6 - 10-7 mol/L,weaker than Ag-Ab interactions

    Lectins are proteins that recognize saccharides, their interaction help mediate cell-cell interaction, making a cell cluster. Virus, bacteria and small organisms use this mechanism to recognize and invade cells.

    Weak interactions, much weaker than antigen-antibody, as shown by low dissociation constant. Thats why its taken long to understand carbohydrates

  • Glycoproteins &Glycolipids

    Cell-cell adhesion

    Cell-cell interaction

    fertilization immunity infection cancer

    QC, trafficking, sorting

    Carbohydrates in quality control, ensuring if proteins are properly folded.

    If not properly folded, not secreted and caught in trafficking, they are stored in endoplasmic reticulum and modified. At times its carried to proteosomes and broken down

  • Different blood types due to presence of different types of glycans

    In type A, N-acetyl galactosamine linked to galactose

    In type B, galactose linked to galactose

    different ppl have different blood types as genes code for different types of enzymes

  • More complex!

  • Cell surface proteoglycans

    Another class of molecules with lots of carbohydrates. So, carbohydrates seem to be the parent structure

    The name has all to do with history. Now many proteoglycans have been found with less carbohydrate parts

    Syndecan refers to protein part of molecule, i.e. protein part is binded to cell membrane

  • Proteoglycans in the extracellular matrix

    Extracellular proteoglycans serve as lubricants in synovial joints

    ones sticking out in red are glycan structures

    Aggrecan and Versican are attached to a molecule of large molecular weight (hyaluronan) and used in ECM

  • Glycosminoglycans DRUs tetrasaccharide - serine

  • Glycans Bonds between

    saccharide units

    Form

    Cellulose -1,4 glycosidic bond linking Glc residues

    Linear

    Chitin -1,4 glycosidic bond

    linking GlcNAc res

    Linear

    Glycosaminoglycans

    hyaluronan Disaccharide repeats of GlcUA and GlcNAc, linked via alternating -1,4 and -1,3 glycosidic bonds

    Linear

    Structural polysaccharides

    complexity comes about by linkages

  • Glucans Bonds between glc residues

    Form Repeating glc units

    Starch

    amylose -1,4 glycosidic bond linear

    1000

    4000

    amylopectin-1,4 glycosidic bond

    -1,6 glycosidic bond

    Linear

    branched

    20 25 per segment

    Glycogen -1,4 glycosidic bond

    -1,6 glycosidic bond

    Linear

    branched

    12 18 per segment

    Storage polysaccharides energy store

  • A segment of amylose

  • A segment of amylopectin

  • What strategies are used to release glucose units from

    dietary vs stored glycogen?

    Extracellular digestion ()

    Intracellular digestion (, , )

  • Enzymatic cleavage

    starch can be used as storage molecule as it has many enzyme cleavage site. It has many reducing ends which can be attacked to release glucose..... helps break up food

    Alpha amylase is for extra cellular digestion

    Enzymes that attack non-reducing ends are controlled by hormones.

    Intra cellular digestion is highly regulated, attacks non-reducing end only

    Debranching enzymes are inside the cell

  • Fates of digestion products Glucose from amylase action in gut lumen

    Intestinal absorption, delivery via hepatic portal vein

    Transport into hepatocytes

    In hepatocytes, glycolysis .ATP

    or glycogenesis ..storage in cells

    Glucose 1-phosphate, from glycogen phosphorylase action in liver cells or myocytes

    Isomerization to Glc 6-phosphate, then glycolysis

    ATP

  • Back to Basics

  • aldehyde group gives reducing property

    4 carbon structure built by adding carbon, sp2 hybrid, adding carbon from top or bottom, gives 2 isomers

    Glucose and Mannose differ at carbon-2 only. They are said to be epimeric at carbon number 2 and are epimers of one another

    Glucose and Galactose epimeric at C-4

  • Monosaccharides

    Glucose, galactose, mannose Aldohexoses aldehyde group at C-1

    Glc and man epimeric at C-2

    Glc and gal epimeric at C-4

    Fructose Ketohexose ketone group at C-2

    Glc and fru are structural isomers.

    Ribose Aldopentose aldehyde group at C-1

    ..linking by glycosidic bonds

  • alpha and beta structures also due to ablove and below attack, alpha above

    sucrose is a non-reducing sugar as anomeric carbon is not free. The others have a reducing end, anomeric carbon is free

  • Towards new therapeutics

    Infection by influenza virus

    Drugs that inhibit neuraminidase prevent propagation of the virus

    Inflammatory diseases

    Drugs to perturb selectin-sugar ligand interactions interfere with recruitment of leukocytes

    not covered in lecture

  • Influenza virus and therapeutic targets (1)

    Hemagglutinin (HA)

    HA binds to sialic acid residues on

    surface glycoproteins of host cells and

    triggers internalization of virus

    Neuraminadase (NA)

    NA cleaves sialic acid residues off

    surface glycoproteins of host cells and

    faciliatates viral propagation

    M2 Ion Channel

    Proton-selective ion channel lowers

    the pH inside of the virus resulting in

    dissociation of the RNPs from the

    matrix protein (M1)

    Ribonucleoprotein (RNP)

    An independent transcription active

    unit (containing a polymerase complex)

    packaged in nucleoprotein

    www.cdc.gov/h1n1flu/yearinreview/yir1.htm

    not covered in lecture

  • Mukhopadhyay et al. Nature Reviews Microbiology 3, 13-22 (2005)

    Haemaglutinin binds sialic acid residues on host cell

    surface glycoproteins

    Neuraminidase cleaves sialicacid residues off host cell surface glycoproteins

    not covered in lecture

  • Influenza virus targets of therapeutic intervention

    von

    Itz

    ste

    in N

    atu

    re R

    evie

    ws D

    rug

    Dis

    covery

    6,

    96

    7-9

    74 (

    2007)

    Amantadine

    Amantadine

    Ribavarin

    Zanamivir,

    oseltamivir

    not covered in lecture

  • O-linked glycans

    not covered in lecture

  • (1)

    (2)

    not covered in lecture

  • not covered in lecture


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