Carbohydrates are ubiquitous modifications of eukaryotic cell surface proteins and lipids.

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Carbohydrates are ubiquitous modifications of
eukaryotic cell surface proteins and lipids.
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Glycans
Localization of glycoconjugates in intracellular
and extracellular compartments
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Glycans
Functions
Extrinsic functions resulting from glycan-lectin
interactions
Intrinsic functions performed by glycans
Directing trafficking of glycoconjugates Intracel
lular Extracellular Mediating and modulating
cell adhesion Cell-cell interactions Cell-matrix
interactions Mediating and modulating
signaling Intracellular Extracellular
Providing structural components Cell
walls Extracellular matrix Modifying protein
properties Solubility Stability
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Glycans Structures
Three major classes of glycoconjugates
Attached to proteins through a nitrogen atom
of asparagine (N-linked) through an oxygen
atom of serine or threonine (O-linked)
Attached to lipids
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Glycans Structures
Glycans are composed of monosaccharides with
related chemical structures
Glucose
Galactose
Hexoses are the most common constituents of
glycans
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Glycans Structures
Two ways to form a pyranose (6-member) ring from
glucose
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Glycans Structures
Substitution of the 2-hydroxyl group of glucose
or galactose with acetamido group yields
N-acetylhexosamines
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Glycans Structures
Common derivatives of the hexoses
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Glycans Structures
Structure of N-acetylneuraminic acid, the most
common form of sialic acid
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Glycans Structures
Glycosidic linkages between monosaccharides exist
in multiple configurations
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Glycans Structures
A typical N-linked glycan
Chemical structure
Word structure
Symbol structure
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Glycans Structures
Formation of glycosidic linkages require energy
and catalyzed by specific enzymes,
glycosyltransferases
Glycosyltransferase reaction
UDP-galactose, an example of a nucleotide sugar
donor
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Glycans Structures
Understanding structure-function relationship for
glycans can be more difficult than for other
classes of biopolymers
The functions of polypeptide and glycan
portions of glycoproteins are potentially
independent
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Glycans Structures
Understanding structure-function relationship for
glycans can be more difficult than for other
classes of biopolymers
Monosaccharides generate more linkage
variation than amino acids or nucleotides Examp
le structure of variations
3 nucleotide bases
6 3 amino acids 6
3 hexoses 1,056 - 27,648
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Glycans Structures
Glycan structures are encoded indirectly in the
genome
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Glycans
Functions
Extrinsic functions resulting from glycan-lectin
interactions
Intrinsic functions performed by glycans
Directing trafficking of glycoconjugates Intracel
lular Extracellular Mediating and modulating
cell adhesion Cell-cell interactions Cell-matrix
interactions Mediating and modulating
signaling Intracellular Extracellular
Providing structural components Cell
walls Extracellular matrix Modifying protein
properties Solubility Stability
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I. Heparan sulfate proteoglycans
Disaccharide unit
Sulfate IdoA
Large O-linked chains of as many as a hundred
residues
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Abnormalities in heparan sulfate biosynthesis is
implicated in the human multiple exostoses
syndrome
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II. Notch signaling Notch proteins
mediate a wide variety of cell fate decisions
during development in Drosophila -
Organogenesis and pattern formation -
Neurogenesis - Myogenesis - Oogenesis -
etc. Malfunctioning of Notch signaling
causes - Human T-cell lymphoblastic leukaemia
(TAN-1/Notch1) - Human stroke and dementia
(CADASIL, Notch3) - Spondylocostal dysostosis
(Dll3) - Alagille syndrome (Jagged1) - Murine
breast cancer (int-3/Notch4)
in Vertebrates (4 Notch genes, 5 ligands) -
Somitogenesis - Neurogenesis - T-cell
development - etc.
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Fringe
O-fucose
Serrate
Notch
Delta
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Glycans
Functions
Extrinsic functions resulting from glycan-lectin
interactions
Intrinsic functions performed by glycans
Directing trafficking of glycoconjugates Intracel
lular Extracellular Mediating and modulating
cell adhesion Cell-cell interactions Cell-matrix
interactions Mediating and modulating
signaling Intracellular Extracellular
Providing structural components Cell
walls Extracellular matrix Modifying protein
properties Solubility Stability
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III. O-mannosylation in muscular dystrophies
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Normal muscle
Muscular dystrophy
Basal Lamina
Neurexin
Neurexin
Laminin
Laminin
Agrin
Agrin
O-mannosyl glycans
Extracellular
a
a
Dystroglycan
Dystroglycan
b
b
Membrane
Dystrophin
Dystrophin
Intracellular
Actin-filament
Actin-filament
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Functions III. O-mannosylation in muscular
dystrophies
Compromised O-mannosylation of dystroglycan
causes severe muscle and brain abnormalities
Muscle biopsy Dystrophic changes
Example Muscle-eye-brain disease congenital
muscular dystrophy, severe congenital myopia,
hydrocephalus, mental retardation
Cranial MRI Cerebellar hypoplasia Neuronal
migration disorder
Yoshida et al., Dev. Cell 2001
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Muscular dystrophies associated with mutations in
glycosyltransferase genes.
Condition Gene Protein function Clinical features
Muscle-eye-brain disease (MEB) O-mannose-b-1,2-N-acetylglucosaminyltransferase (POMGnT1) O-mannosyl glycan synthesis Severe muscle weakness Mental retardation Epilepsy Neural migration disorder Ocular abnormalities
Fukuyama congenital muscular dystrophy (FCMD) Fukutin Putative glycosyltransferase Severe proximal and axial weakness Mental retardation Epilepsy Neural migration disorder
MDC1C and LGMD21 Fukutin related protein (FRP) Putative glycosyltransferase Variable proximal and axial muscle weakness Cardiomyopathy
Walker Warburg syndrome (WWS) Protein O-mannosyltransferase 1 2 (POMT1 and POMT2) O-mannosyltransferase Severe muscle weakness Death in infancy Absent psychomotor development Neural migration disorder Ocular abnormalities
Rotated abdomen (rt) and twisted (tw) in Drosophila Protein O-mannosyltransferase 1 (POMT1) O-mannosyltransferase Disrupted myogenesis
Myodystrophy mouse (myd) LARGE Putative glycosyltransferase Muscle weakness Neural migration disorder
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Glycans Functions
IV. ABO blood groups (1900s, Landsteiner et
al.)
IO IA IB
Alleles Encode glycosyltransferases
Inactive GalNAc-transferase
Gal-transferase
The glycan antigens are expressed on the surface
of red blood cells and determine the
compatibility in blood transfusions
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Glycans
Directing trafficking of glycoconjugates Intracel
lular Extracellular Mediating and modulating
cell adhesion Cell-cell interactions Cell-matrix
interactions Mediating and modulating
signaling Intracellular Extracellular
Providing structural components Cell
walls Extracellular matrix Modifying protein
properties Solubility Stability