Chapter 4 glycosylation precursors
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Chapter 4 Glycosylation Precursors. Ya -Min Chi. Intro. Glycosylation requires activation of monosaccharides to nucleotide sugar. Nucleotide sugar is the high-energy donor form. Activated Form. Glucose Transporters. Three types Energy-independent diffusion transporter

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Chapter 4 Glycosylation Precursors

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Chapter 4 glycosylation precursors

Chapter 4 Glycosylation Precursors

Ya-Min Chi


Intro

Intro

  • Glycosylation requires activation of monosaccharides to nucleotide sugar.

  • Nucleotide sugar is the high-energy donor form.


Activated form

Activated Form


Glucose transporters

Glucose Transporters

  • Three types

    • Energy-independent diffusion transporter

      • e.g. Hexose transporter

    • Energy-dependent transporter

      • e.g. Sodium-dependent glucose transporter (SGLT)

    • Transporter that couple ATP phosphorylation with sugar import.

      • e.g. found in bacateria


Mannose fucose transport

Mannose & Fucose Transport

  • Mannose

    • Energy-dependent transporter

      • Near border of enterocytes

      • Surface of kidney tubule epithelial

    • Energy-independent facilitated diffusion

      • Surface of many mammalian cells

  • Fucose

    • Found in several type of mammalian cells

    • Km-250µM


Intracellular source of monosaccharides

Intracellular Source of Monosaccharides

  • Salvage

    • from glycoconjugates

      • Degradation at low pH in the lysosomes

    • Lysosomal carriers

      • Neutral sugar carrier

        • Km-50-75mM

      • N-acetylhexosamine carrier

        • Km-4mM

      • Acidic sugar carrier

        • Km-300-550µM


Activation and interconversion

Activation and Interconversion

  • Glycogen

    • Glycogenin

    • Glycogen phosphorylase

    • From UDP-Glc

  • Glucose

    • Building block of other sugar

      • Glycogen

      • Glucosylceramide

      • Dolichol-P-glucose


Chapter 4 glycosylation precursors

  • Glucuronic Acid

    • UDP-GlcA

      • Synthesized from UDP-GlC

      • For

        • GAG biosynthesis

        • Some N-/O-linked glycans and glycosphingolipids

  • Iduronic Acid

    • C-5 epimer of glucuronic acid

    • Found in GAGs, dermatan sulfate, heparan sulfate, and heparin

    • Created from epimerization of GlcA


Chapter 4 glycosylation precursors

  • Xylose

    • UDP-Xyl

      • Created from decarboxylation of UDP-GlcA

      • Initiate GAG synthesis

  • Mannose

    • Use for multiple types of glycan

    • GDP-Man

      • Primary activated donor

      • form Lipid-linked oligosaccharide on ER

      • Form dolichol-P-mannose in the ER membrane

  • Fucose

    • GDP-Fuc

      • From GDP-Man or directly from fucose


Chapter 4 glycosylation precursors

  • Galactose

    • UDP-Gal

      • From Gal or UDP-Glc

  • N-Acetlyglucosamine

    • UDP-GlcNAc

      • From fructose or GlcNAc

  • N-Acetlygalactosamine

    • UDP-GalNAc

      • From GalNac or epimerization of UDP-GlcNAc

  • Sialic Acids

    • CMP-Sia

      • Many ways to obtain

      • Mostly occur in Golgi


Bacteria and plant

Bacteria and Plant

  • Animal

    • Fucose

      • The only deoxyhexoes in animal cell glycan

  • Bacteria and Plant

    • Varieties of sugars

      • Deoxysugars

        • From oxidation of C-4

      • Deoxyaminosugars

        • Amino sugar- from keto sugar with addition of amino group from glutamine

      • Branched-chain sugars


Nucleotide sugar transporters

Nucleotide Sugar Transporters

  • Activated sugar must be transport

    • Needed in ER and Golgi

    • Negatively charged

  • Antiporters

    • Energy-independent

    • Organelle specific

    • Location correspond to glycosyltranferases’ location

    • Km-1-10µM

    • Export nucleoside monophosphates


Control of nucleotide sugar levels

Control of Nucleotide Sugar Levels


Other modification

Other Modification


Carrier lipids

Carrier Lipids

  • Transport sugar for glycosylation

  • e.g.

    • Undecaprenyl-P

    • Dolichol-P


Chapter 5 glycosyltransferases and glycan processing enzymes

Chapter 5Glycosyltransferasesand Glycan-processing Enzymes


Intro1

Intro

  • Glycosyltransferases

    • Transport sugar from nucleotide sugar to substrate

    • Variety of enzymes

  • Glycosidase

    • Enzyme that break down glycosidic bond

    • For the formation of N-glycans

  • Other enzymes

    • e.g. sulfotransferases


Glycosyltransferase specificity

Glycosyltransferase Specificity

  • “one enzyme-one linkage”

    • Exception

      • some enzymes can produce the same linkage

        • e.g. human fucosyltransferases III-VII

      • Some have two separate active sites


Protein glycoprotein acceptors

Protein/Glycoprotein Acceptors

  • Specificity of glycosylation reaction

    • Polypeptide chain of acceptor

    • Folding of protein acceptor


Glycosyltransferase sequence families

GlycosyltransferaseSequence Families

  • Represent 1-2% of the genome

  • 30,000+ sequence

  • 90 families

    • 29 families’ structures have been determined


Folding type

Folding type

  • Two major types of of folding

    • GT-A

      • One single domain

      • Contain Rossmann fold

      • Contain DXD motif (asp-any residue-asp)

      • Metal-ion dependent

    • GT-B

      • Two domains

        • One is carboxy-termminal

      • Metal-ion independent


Catalytic mechanisms

Catalytic Mechanisms

  • Through either inversion or retention of stereochemistry at the anomeric carbon.

inversion


Kinetic mechanisms

Kinetic Mechanisms

  • Bi Bi sequential kinetic mechanism

    • Donor substrate is bind first

    • Acceptor is release first


Other enzymes

Other Enzymes

  • Sulfotransferases

    • Cytoplasm and the Golgi

    • For glycosaminylglycans

      • Embryological development and physiology

    • For L-selectin ligand

      • Trafficking of lymphocytes

    • Use PAPS as sulfate donor


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