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Essentials of Glycobiology Lecture 33 May 28, 2002 Jeff Esko

Essentials of Glycobiology Lecture 33 May 28, 2002 Jeff Esko. Bacterial Polysaccharides: Structure, Biosynthesis, Biological Functions and Significance …or I never met a glycan I didn ’ t like. Overview. General structure of bacterial cell walls

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Essentials of Glycobiology Lecture 33 May 28, 2002 Jeff Esko

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  1. Essentials of Glycobiology Lecture 33May 28, 2002Jeff Esko Bacterial Polysaccharides: Structure, Biosynthesis, Biological Functions and Significance …or I never met a glycan I didn’t like

  2. Overview • General structure of bacterial cell walls • Structure, function and assembly of peptidoglycan (murein) • Periplasmic -glucans (MDO) • Lipopolysaccharide (LPS) - endotoxin • Capsular polysaccharides - mimicry • Bacterial glycoproteins - a new area

  3. Capsule LPS PG MDO

  4. A A A A D D D D G G G G A A A A A A A A G G G G D D D D A A A A A A A D D D G G G A A A A A A A G G G G D D D D A A A A A A A A D D D D G G G G A A A A A A A A G G G G D D D D A A A A Peptidoglycan [GlcNAcb1,4MurNAcb1,4]n Heijenoort (2001) Glycobiology 11:25R

  5. C H O H C H O H 2 2 O O O O O O O H C C H N H A c N H A c 3 O C L - A l a D - G l u D A P D - A l a D - A l a Murein Glycopeptide Notice D-amino acids DAP = diaminopimelic acid

  6. A A A A D D D D G G G G A A A A A A A A G G G G D D D D A A A A A A A D D D A A A A G G G A A A A A A A G G G G D D D D A A A A A A A A D D D D G G G G A A A A A A A A G G G G D D D D A A A A Peptidoglycan The final step involves cleavage between the D-Ala-D-Ala unit and transpeptidation to the amino group of DAP of another unit

  7. Vancomycin

  8. Monenomycins

  9. P Peptidoglycan Biosynthesis Undecaprenyl phopsphate

  10. MDO

  11. Membrane Derived Oligosaccharides (MDO) • Branched -glucans • Represent about 1-5% of dry weight • Charged substituents act as an osmolyte and protects the inner membrane against the large difference in osmolarity inside the cell compared to outside the cell

  12. LPS

  13. Lipopolysaccharide (LPS) • LPS consists of three domains • Lipid A, otherwise known as endotoxin • Core region composed of KDO (K), heptoses (H), and hexoses (open hexagons • Highly variable outer O-antigen region

  14. H O O H H O H O H O U r i d i n e U r i d i n e N H AcN O H O H O H O H H O H O O O O O O O O P P P P O O O C O O O O O • Initiates by acylation of UDP-GlcNAc at C3, followed by N-deacetylation, and N-acylation Wyckoff et al. (1998) Trends Microbiol. 6:154

  15. O H O H O H C H 2 O O O O H O O O H O H O O O O O O H O O U r i d i n e N H P P N H N H O P O C O O O C O O C O O N H P O O H O H O O O C O O H O O O H H O H O H O H O H O H O H O H O Lipid A Assembly + Diacylglucosamine-1-P condenses with another molecule of UDP-diacylglucosamine to form the tetraacyl disaccharide core

  16. Lipid A Assembly • KDO transferases initiate the formation of the core • Additional C12 fatty acids added to -hydroxy groups (wax) • Lipid A translocates to the outer leaflet of the outer membrane by msbA (ABC transporter) Doerrler et al. (2001) J Biol Chem. 276:11461

  17. Lipid A Biology • Lipid A, the heat stable endotoxin of gram negatives • Resistant strains of mice defined a locus, lps, which as positionally cloned. This turned out to be homologous to toll receptors in Drosophila, which were known to be involved in innate immunity to fungal infection (anitmicrobial peptides) • lps turns out to beTlr4, a member of a family of signaling receptors (10 members known) that induce . Tlr4 binds to Lipid A. Tlr2 apparently binds and responds to muramyl-dipeptide

  18. Takeda & Akira(2001)Genes to Cells 6:733

  19. LPS Structural and Functional Domains

  20. C H O H 2 C H O H 2 H O H C C H O H O C O O H O H O O H O H O H O H O H O H Core region contains unusual sugars 3-deoxy-D-manno-octulosonic acid (KDO) L-glycero-D-manno- heptulose • The inner core contains 1-4 KDO residues, which look like an analog of sialic acid. • The core also contains heptopyranoses, which can vary stereochemically • The rest of the core consists of various combinations of Glc and Gal

  21. LPS Structural and Functional Domains

  22. O-antigens • O-antigens consist of 2-8 sugars, repeated ≤50 times • O-antigens gives rise to different serotypes and some are correlated with disease

  23. Capsule

  24. Mucoid strains contain a polysaccharide capsule • >80 different capsules types are known just in E. coli • Extraordinary diversity of structure

  25. Mycobacteria Crick et al. (2001) Glycobiology 11:107R

  26. Crick et al. (2001) Glycobiology 11:107R

  27. Bacterial Glycoproteins • Surface-layer (S-layer) glycoproteins • Prevalent in Bacteria and Archaea, but structures differ, e.g., N-linked glycosylation only in Archaea • Structural analyses have revealed unusual carbohydrate-linkage regions…. • ….and unusual nucleoside diphosphate-linked oligosaccharides

  28. Schaffer et al (2001) Proteomics 1:248

  29. Notice diversity of linkages Similarity in sequence of N-linked attachment sites and mechanism of assembly of glycan (dolichol pathway) Burda &Aebi (1999) Biochim Biophys Acta 1426:239

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