Essentials of Glycobiology Chapter 1: Historical Background and Overview Alexander Hsieh

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Essentials of Glycobiology
Chapter 1: Historical Background and Overview
Alexander Hsieh
Overview
• Historical Background of the Field of Glycobiology
• General Terms and Definitions
• Common Monosaccharide Units of Glycoconjugates
• Nomenclature and Symbols in Structural Depictions
• General Oligosaccharide Classes
• Biological Implications Related to Synthesis and Function
Historical Background
What is Glycobiology?
•Central Dogma of molecular biology: DNA ->RNA ->Protein
• Common incorrect (why?) extrapolation: DNA -> RNA -> Protein -> cell -> organism
• All cells in nature carry Oligosaccharides and Glycans in a dense and complex way
• Corrected “New Dogma”:
Historical Background cont’d
• Why was there a need for a new dogma?
• Study of glycans lagged behind other major classes:
• Inherent structural complexity
• Difficulty of sequence determination
• Biosynthesis cannot be predicted directly from DNA template
However…
• In 1988, Rademacher, Parekh, and Dwek recognized the coming together of several
traditional disciplines and coined the term “Glycobiology”
Formal Definition:
• Glycobiology: the study of the structure, biosynthesis, and biology of saccharides
(sugar chains or glycans) that are widely distributed in nature and the proteins that
recognize them
• Universal Principles of Glycobiology
General Terms and Definitions
• Carbohydrate: Polyhydroxyaldehydes or polyhydroxyketones or larger
compounds that can be hydrolyzed into such units
• Monosaccharide: Carbohydrates that cannot be hydrolyzed into simpler units
• Oligosaccharides: Branched or linear chains of monosaccharides attached by
glycosidic linkages
• Glycosidic Linkage: Attachment of monosaccharides to one another through
the hydroxyl group at the chiral center
• Glycoconjugate: A compound in which one or more monosaccharides or
oligosaccharides (“glycones”) are covalently linked to a noncarbohydrate
functional group (“aglycone”)
Common Monosaccharide Units of Glycoconjugates
• Pentoses: 5-carbon sugars
• Ex: D-xylose (Xyl)
• Hexoses: 6-carbon neutral sugars
• Ex: D-glucose (Glc), D-galactose (Gal), or D-mannose (Man)
• Hexosamines: Hexoses with an amino group at the 2-position
• Ex: N-acetyl-D-glucosamine (GlcNAc), N-acetyl-D-galactosamine (GalNAc)
• Deoxyhexoses: 6-carbon neutral sugars with a hydroxyl group at the 6-position
• Ex: L-fucose (Fuc)
• Uronic Acids: Hexoses with negatively charged a carboxylate at the 6-position
• Ex: D-gluronic Acid (GlcA) or L-iduronic Acid (IdA)
• Sialic Acids: Family of 9-carbon acidic sugars
• Ex: N-acetylneuraminic acid (Neu5Ac)
Nomenclature
and Symbols in
Structural
Depictions
•
Isomers
differentiated by
color/black/white/sha
ding
•
Modifications to
monosaccharide
units are listed
before the name
•
Numbers represent
linkages
•
Same shading/color
used for different
monosaccharides
with same
stereochemistry
General Oligosaccharide Classes
• Glycoproteins
• Defined as glycoconjugates in which a protein carries one or more glycans
covalently attached to a polypeptide backbone, usually by N- or O- Linkages
• N-Glycans (N-linked oligosaccharides or N-(Asn)-linked)
• Defined as a sugar chain covalently linked to an asparagine residue of a
polypeptide chain; follows the sequence:
• Asn – X – Ser/Thr
• O-Glycans (O-linked oligosaccharides or O-(Ser/Thr)-linked)
• Typically linked to the polypeptide via N-acetylgalactosamine (GalNAc) to a
hydroxyl group of a serine or threonine residue
• Proteoglycan
• Defined as a glycoconjugate that has one or more glycosaminoglycan (GAG)
chains attached to a core protein through a region ending in a xylose residue
linked to the hydroxyl group of a serine residue
General Oligosaccharide Classes cont’d
• Glycophosphatidylinositol Anchor
• Defined as a glycan bridge between phosphatidyliniositol and a
phosphoethanolamine that is in amide linkage to the carbxyl end of a protein;
constitutes the only anchor to the lipid bilayer membrane for the proteins
• Glycosphingolipid (GSL, or glycolipid for short)
• Consist of a glycan attached via glucose or galactose to the terminal primary
hydroxyl group of the lipid functional group ceramide (composed of a long chain
base (sphingosine) and a fatty acid)
Biological Implications related to Synthesis and Function
• Most biosynthesis of glycans confined within ER and Golgi
compartments, much synthesis takes place internally
• Most newly synthesized proteins originating from the ER are modified by
glycosyltransferases at various stages while traveling to their final destination,
allows for much diversity
• Like all components of living cells, glycans are constantly being synthesized,
used, then degraded (the turnover); circle of life
• Glycan function falls into 2 categories:
• Structural and Modulatory functions
• (involve the glycans themselves or or their movulation of the molecules to which they
are attached)
• Specific recognition of Glycans by Glycan-Binding Proteins
• (can lead to glycan-protein interactions central to the processes of the organism)
• The field of Glycobiology is constantly evolving
• Elucidation of additional glycan function/synthesis leads to important
discoveries relevant to areas such as Genetics, Evolutionary Biology,
Medicine, and Biotechnology.
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