lecture012909 - Glycans linked to lipids lipid precursors...

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Glycans linked to lipids, lipid precursors, and glycans in N-linkage to protein 1/29/07
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Large O-linked Glycosaminoglycans and poly- lactosamine structures Glycoprotein N-linked and O- linked oligosaccharides Glycolipid oligosaccharides
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Glycan synthesis in a cellular context
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Overview From ER through Trans-Golgi and points inbetween
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On and into the ER Dolichol-P-X Glycosyl phosphatidylinositol (GPI) Glycosphingolipids (GSL)
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Schenk, B. et al. Glycobiology 2001 11:61R-70R; doi:10.1093/glycob/11.5.61R Topological model for the enzymatic reactions leading to Dol-P biosynthesis de novo on the cytoplasmic face of the ER
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Biosynthesis of N-Glycans: Production of GlcNAc-P-P-Dolichol Adapted from Marquardt T, Denecke J. Eur J Pediatr. 2003 Jun;162(6):359-79 GlcNAc Man Gal Sia Fuc Glc Dolichol Tunicamycin Blocks - not very specific!
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Biosynthesis of the N-Glycan Precursor on the Cytosolic Leaflet of the Endoplasmic Reticulum (ER) Adapted from Marquardt T, Denecke J. Eur J Pediatr. 2003 Jun;162(6):359-79 GlcNAc Man Gal Sia Fuc Glc CDG = Congenital Disorder of Glycosylation in Humans
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Biosynthesis of the N-Glycan Precursor on Lumenal Leaflet of ER Adapted from Marquardt T, Denecke J. Eur J Pediatr. 2003 Jun;162(6):359-79 GlcNAc Man Gal Sia Fuc Glc
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Completion of Biosynthesis of N-Glycan Precursor on Lumenal Leaflet of ER - and Transfer to Protein Adapted from Marquardt T, Denecke J. Eur J Pediatr. 2003 Jun;162(6):359-79 GlcNAc Man Gal Sia Fuc Glc
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Schenk, B. et al. Glycobiology 2001 11:61R-70R; doi:10.1093/glycob/11.5.61R Topological model for lipid intermediate synthesis, translocation and the role for Dol-P-P/Dol-P phosphatases in the recycling of Dol-P-P/Dol-P in the ER
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ER glycolipid synthesis Dolichol-P-X Glycosyl phosphatidylinositol (GPI)
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Examples of GPI-Anchored Proteins Cell surface hydrolases alkaline phosphatase acetylcholinesterase 5 ʼ nucleotidase Adhesion molecules neural cell adhesion molecule heparan sulfate proteoglycan Others decay accelerating factor scrapie prion protein folate receptor Protozoal antigens trypanosome VSG leishmanial protease plasmodium antigens Mammalian antigens Thy-1 carcinoembryonic antigen After Hart, G
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Structure of the Basic GPI Anchor Etn P INOSITOL P = Mannose (Man) = Glucosamine Etn = Ethanolamine P = Phosphate NH 2 NH 2 Pig-A PNH Defect GPI-Linked Protein Cell Surface Membrane After Hart, G
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Structural Analysis of the GPI Anchor Enzymatic and chemical cleavage sites are useful in identifying GPI anchored membrane proteins After Hart, G
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After Freeze, H
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Biosynthesis of GPI anchors • The first step in biosynthesis of the GPI anchor requires at least four genes • One of them, PIG-A is an X-linked gene Mutation in PNH MUTATIONS IN DOL-P-MAN SYN AND USE After Freeze, H
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Paroxysmal Nocturnal Hemoglobinuria A hematopoietic stem cell disorder characterized by intravascular hemolytic anemia. Abnormal blood cells lack GPI-anchored proteins due to a mutation in the PIG-A gene.
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