1. Glycoconjugates ( excluding Glycoproteins) Glyco-Chemistry and the PDB

2. ABL 5-amino-5-deoxy-cellobiono-1,5-lactam di-saccharide CBI CELLOBIOSE di-saccharide CE5 CELLOPENTAOSE penta-saccharide CE6 CELLOHEXAOSE hexa-saccharide CE8 CELLOOCTAOSE octa-saccharide CTR CELLOTRIOSE tri-saccharide CTT CELLOTETRAOSE tetra-saccharide DCB 2,4-DINITROPHENYL-2-DEOXY-2-FLUORO- BETA-D-CELLOBIOSIDE di-saccharide FCT DEOXY-2-FLUORO-B-D-CELLOTRIOSIDE tri-saccharide FFC 2-DEOXY-2-FLUORO-B-D-CELLOBIOSIDE di-saccharide RCB "p-nitrophenyl beta-D-cellotrioside" tri-saccharide TCB THIOCELLOBIOSE di-saccharide CELLULOSE Fragments in PDB http://en.wikipedia.org/wiki/Cellobiose http://en.wikipedia.org/wiki/Cellulose

3. Chitin long-chain polymer of a N-acetylglucosamine, main component of the cell walls of fungi, the exoskeletons of arthropods and insects http://en.wikipedia.org/wiki/Chitin

4. CTO TRIACETYLCHITOTRIOSE tri-saccharide GUM 4-METHYL-UMBELLIFERYL-N-ACETYL-CHITOBIOSE di-saccharide Umbelliferone can be used as a fluorescence dye CTO GUM http://en.wikipedia.org/wiki/Umbelliferone

5. Glycoconjugates  Covalent bond between carbohydrate and biomolecule  Glycoproteins  Glycolipids  Function of oilgosaccharides:  Structural  Hydrophilic (protein surface)  Limit conformations  Reactivity  Shield surface and affect reactivity  Surface Recognition  Label proteins  Intracellular communication http://en.wikipedia.org/wiki/Glycoconjugate

6. 1. Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). Ser- linked and consist of long, unbranched chains of alternating residues of hexosamine and uronic acid or galactose, often sulfated found mainly in connective tissues http://en.wikipedia.org/wiki/Proteoglycan Glycoproteins: 2 types(?) 2. Glycoproteins are proteins that contain oligosaccharide chains (glycans) covalently attached to polypeptide side-chains. N- glycosylation and O-glycosylation with comparatively small, branched, usually unsulfated carbohydrate units, devoid of repeating units. http://en.wikipedia.org/wiki/Glycoprotein Proteoglycans have not been considered as glycoproteins because their carbohydrate seemed to differ so greatly

7. ProteoglycansGlycoproteins Carbohydrate Composition = up to 97% Carbohydrate Composistion = 1- 60% 1-100’s of GAG chainsShort, branched, N and O-linked carbohydrate chains < 20 residues GAG chains of 80 sugarsMixture of sugars No sialic acidOften terminal sialic acid Up to 3 x 10 KdUp to 2 - 300 Kd GAG Glycosaminoglycan http://en.wikipedia.org/wiki/Glycosaminoglycan

8. Non-toxic: Flavonoids Toxic: Cyanogennic glycosides Anthocyans Tannins Saponin that form soapy lathers when mixed and agitated with water, used in detergents, foaming agents, and emulsifiers. http://en.wikipedia.org/wiki/Saponin Coumarins produced synthetically and widely used in perfumes. Simple Glycoconjugates: Glycosides are widely distributed in plants The most important glycosides: http://en.wikipedia.org/wiki/Glycoside

9. DGX DIGOXIN digitalis, is a purified cardiac glycoside and extracted from the foxglove plant PDB entry has only mono-saccharide part http://en.wikipedia.org/wiki/Digoxin

10. http://en.wikipedia.org/wiki/Ouabain Related PDB OBN OUABAIN poisonous cardiac glycoside http://en.wikipedia.org/wiki/Cardiac_glycoside

11. RUT RUTIN di-saccharide citrus flavonoid glycoside inhibits platelet aggregation http://en.wikipedia.org/wiki/Rutin

12. FSC Fusicoccin Fungal Toxin http://en.wikipedia.org/wiki/Fusicoccin

13. Glycosaminoglycans

14. Proteoglycans

15. 3hya HYALURONIC ACID GCU NAG BDP NAG BDP NAG BDP NAG 1kes KERATAN SULPHATE G6S NGS 1aga AGAROSE GAL AAL GAL AAL GAL AAL 1c4s CHONDROITIN-4-SULFATE GC4 ASG GCU ASG GC4 ASG 1cap CAPSULAR POLYSACCHARIDE MAN BGC BDP GAL MAN CEG 1car I-CARRAGEENAN G4S DGS G4S DGS G4S DGS 2c4s CHONDROITIN 4-SULFATE GCU ASG 2hya HYALURONIC ACID GCU NAG GCU NAG 4hya HYALURONIC ACID NAG GCU NAG GCU NAG GCU Polysaccharides in PDB Fibre Diffraction

16. http://www.ebi.ac.uk/pdbe/pqs/macmol/1foo.mmol Download expanded fibre diffraction result from TVECT record rasmol 1foo.mmol

17. 1c4s 1kes http://en.wikipedia.org/wiki/Keratan_sulphate http://en.wikipedia.org/wiki/Chondroitin_sulfate Keratan are sulfated glycosaminoglyc ans found in the cornea, cartilage, and bone sulfated glycosaminoglycan (GAG) found attached to proteins as part of a proteoglycan.

18.  Heparin activates antithrombin III (AT-III), a serine protease inhibitor that blocks thrombin and factor Xa in the coagulation cascade. It binds to AT-III very specifically and with high affinity.  However, the composition of this drug, consisting of a highly heterogeneous mixture of polysaccharides, is ill defined.  A synthetic heparin (pentasaccharide) named Fondaparinux, was eventually developed. Heparin http://en.wikipedia.org/wiki/Heparin

19. A portion of the structure of heparin IN PDB H1S "HEPARIN DISACCHARIDE I-S" di-saccharide H3S "HEPARIN DISACCHARIDE III-S" di-saccharide NT1 "HEPARIN HEPTASACCHARIDE" hepta-saccharide NTP "HEPARIN PENTASACCHARIDE" penta-saccharide NTO TRISULFOAMINO HEPARIN PENTASACCHARIDE a glycosaminoglycan most common disaccharide unit is composed of a 2-O-sulfated iduronic acid and 6-O-sulfated, N-sulfated glucosamine, IdoA(2S)-GlcNS(6S)

20. HEPARIN SOLUTION SCATTERING Alternating sulfated- glucosamine & sulfated iduronic acid 3iri (SGN IDS)9 3irj (SGN IDS)12 3irk (SGN IDS)15 3irl (SGN IDS)18

21. Antibiotics 1.Polyketide – Antibiotics 2.Glycopeptide antibiotic 3.Aminoglycoside Anthracycline 4.Glycosidic antibiotics 5.Calichemicins and Esperamicins 6.Aminoglycoside antibiotics Oligosaccharides as drugs

22. Sugar(s) attached to ring system (from 10 to 20 membered ring) Macrolactone, Polyketide - Antibiotics Group 1

23. Polyketide antibiotics, antifungals, cytostatics, anticholesteremic, antiparasitics, coccidiostats, animal growth promoters and natural insecticides are in commercial use http://en.wikipedia.org/wiki/Polyketide NOTE in these slides reference is made to family files e.g. FAM_000087. These are ‘super’ chem-comp CIF files grouping sets of molecules into classes with various properties listed.

24. FAM_000087 & FAM_000407 Chloroorienticin A VANCOMYCIN Decaplanin A40926 Teicoplanin Balhimycin Deglucobalhimycin Glycopeptide antibiotics http://en.wikipedia.org/wiki/Glycopeptide_antibiotic Not all ring systems with sugars attached are Macrolydes

25. Immunosuppressant FAM_000022 587 C32-O-(1-METHYL-INDOL-5-YL)18-HYDROXY-ASCOMYCIN 818 18-HYDROXYASCOMYCIN 858 C32-O-(1-ETHYL-INDOL-5-YL)ASCOMYCIN FK5 8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN FKA BENZYL-CARBAMIC ACID[8-DEETHYL-ASCOMYCIN-8- YL]ETHYL ESTER Ketolide-Macrolide antibiotic FAM_000042 ERY ERYTHROMYCIN A FAM_000037 CAI CARBOMYCIN A FAM_000047 NRB NARBOMYCIN FAM_000055 SPR SPIRAMYCIN I FAM_000067 XBK 4,5-deepoxypimaricin antifungal FAM_000076 E7B TAUTOMYCIN Polyketide inhibitor of the protein phosphatases PP1 and PP2A polyketide macrolactams

26. SPR SPIRAMYCIN I 16-membered ring macrolide aminoglycoside erythromycin- carbomycin group http://en.wikipedia.org/wiki/Spiramycin

27. Glycosylated relatives of anthracycline family that is given as a treatment for some types of cancer e.g. Daunomycin Group 2

28. FAM_000019 BIS-DAUNORUBICIN DAUNOMYCIN 2'-BROMO-4'-EPIDAUNORUBICIN 4-METHYLBENZYL-N-BIS[DAUNOMYCIN] 6-DEOXYDAUNOMYCIN N-HYDROXYMETHYL-N-(2-METHOXYETHYL)-DAUNOMYCIN 4'-EPI-4'-(2-DEOXYFUCOSE)DAUNOMYCIN Aminoglycoside Anthracycline Antineoplastic/Antibiotic http://en.wikipedia.org/wiki/Daunorubicin http://en.wikipedia.org/wiki/Anthracycline

29. Daunomycin intercalated in DNA (PDB ID 1JO2) Aminoglycoside Anthracycline

30. FAM_000002 Aminoglycosides Anthracyclines Antibiotics Antineoplastic DM2 DOXORUBICIN DM6 4'-EPIDOXORUBICIN DM7 4'-DEOXY-4'-IODODOXORUBICIN NOD N-ETHYLHYDROXY-DOXORUBICIN DMM 3'-DESAMINO-3'-(2-METHOXY-4-MORPHOLINYL)-DOXORUBICIN DM4 1-O-DEMETHYL-6-DEOXYDOXORUBICIN 44D 7-[5-(4-AMINO-5-HYDROXY-6-METHYL-TETRAHYDRO-PYRAN-2- YLOXY)-4-HYDROXY-6-METHYL-TETRAHYDRO-PYRAN-2-YLOXY]- 6,9,11-TRIHYDROXY-9-(2-HYDROXY-ACETYL)-7,8,9,10- TETRAHYDRO-NAPHTHACENE-5,12-DIONE CMD 3'-DESAMINO-3'-(3-CYANO-4-MORPHOLINYL)-DOXORUBICIN FAM_000004 oligosaccharide anthracycline, chymotrypsin inhibitor AKA 10-DECARBOXYMETHYLACLACINOMYCIN A AKT 10-DECARBOXYMETHYLACLACINOMYCIN T AKY ACLACINOMYCIN Y FAM_000007 anthracycline Antitumor antibiotic DRA 11-DEOXY-BETA-RHODOMYCIN ERT METHYL (4R)-2-ETHYL-2,5,12-TRIHYDROXY-7-METHOXY-6,11-DIOXO-4- {[2,3,6-TRIDEOXY-3-(DIMETHYLAMINO)-BETA-D-RIBO- HEXOPYRANOSYL]OXY}-1H,2H,3H,4H,6H,11H-TETRACENE-1- CARBOXYLATE

31. DRA http://www.druglead.com/cds/Rhodomycins.html anthracycline Antitumor antibiotic

32. Glycosidic antibiotics e.g. Mithramycin and Chromycin in PDB entries 146d, 207d, 1bp8, 1d83, 1vaq, 1ekh In FAM_000066.cif DNA binding usually represented as LINKed residues http://en.wikipedia.org/wiki/Plicamycin http://en.wikipedia.org/wiki/Neomycin

33. Mg Mithramycin 1 Mithramycin 2 Mithramycin 1 Mithramycin 2 Minor groove Mithramycin Two copies of the molecule binds in the minor groove of the DNA and interacts with it via a Mg ion. (PDB ID 146d) Glycosidic antibiotics

34. Calichemicins and Esperamicins class of potent antitumor antibiotics http://en.wikipedia.org/wiki/Calicheamicin In PDB entries 2l65, 2pik, 1qms, 3oth, 3oti, 2gkc In FAM_000068.cif & FAM_000070.cif (1pik)

35. 2pik Enediyne antibiotic DNA minor groove binder Calichemicins

36. Aminoglycoside antibiotics http://en.wikipedia.org/wiki/Streptomycin Streptomycin in PDB entries 3hav, 1ntb,1nta, 1fjg and in FAM_000056.cif

37. Aminoglycoside antibiotics In PDB entries 1tob, 2tob, 1lc4, 1m4d In FAM_000072.cif http://en.wikipedia.org/wiki/Tobramycin Tobramycin

38. AO3 ALLOSAMIDIN di-saccharide Allosamidin is an inhibitor of both insect and bacterial chitinases. Recently Allosamidin has been reported to be an inhibitor of acidic mammalian chitinase an observation which may have implications in the treatment of asthma. INSECTICIDE

39. e.g. ACR in PDB 1agm, 1esw, 1gah, 1k1y, 1kxh, 1lf9, 1mxd, 1mxg, 1ulv, 2ecp, 2f6d, 2owc, 2oww, 2qmj, 2zq0, 3aic, 3bc9, 3jyr, 3jzj, 3k8m,3pha, 3poc type 2 diabetes mellitus

40. 3SA "ACARBOSE DERIVED TRISACCHARIDE" tri-saccharide 5SA "ACARBOSE DERIVED PENTASACCHARIDE" penta-saccharide 6SA "ACARBOSE DERIVED HEXASACCHARIDE" hexa-saccharide AAO "ACARBOSE DERIVED HEXASACCHARIDE" hexa-saccharide ABC "MODIFIED ACARBOSE HEXASACCHARIDE" hexa-saccharide ABD "ACARBOSE DERIVED HEXASACCHARIDE" hexa-saccharide ACR ALPHA-ACARBOSE tetra-saccharide ARE "ACARBOSE DERIVED PENTASACCHARIDE" penta-saccharide GAC DIHYDRO-ACARBOSE tetra-saccharide IAB ISO-ACARBOSE tetra-saccharide QPS BETA-ACARBOSE tetra-saccharide ACG MODIFIED ACARBOSE PENTASACCHARIDE penta-saccharide Acarbose is an anti-diabetic drug used to treat type 2 diabetes mellitus http://en.wikipedia.org/wiki/Acarbose alpha-amylase inhibitor

41. Glycolipids  Cerebrosides  Galactocerebroside – in neuronal membranes  Glucocerebrosides – elsewhere in the body  Sulfatides or sulfogalactocerebrosides  A sulfuric acid ester of galactocerebroside  Globosides: ceramide oligosaccharides  Lactosylceramide  Gangliosides  Have a more complex oligosaccharide attached  Biological functions: cell-cell recognition; receptors for hormones

42. Any thing that looks vaguely like a Lipopolysaccharide Group 3 Clue look at pdb 1qff

43.  Membrane lipids  Hydrophilic heads are oligosaccharides  Recognition sites Bacterial Lipopolysaccharides

44. LINK N2 PA1 X1000 C1 FTT X1009 LINK C3 PA1 X1000 O1 FTT X1010 LINK O1 PA1 X1000 P1 DPO X2000 LINK N2 GCN X1001 C1 FTT X1011 LINK C3 GCN X1001 O1 FTT X1013 LINK O4 GCN X1001 P PO4 X2001 LINK O3 FTT X1011 C1 DAO X1012 LINK O3 FTT X1013 C1 MYR X1014 LINK O4 GMH X1004 P EAP X2004 LINK O4 GMH X1005 P PO4 X2005 LINK O6 GCN X1001 C2 KDO X1002 LINK C1 GCN X1001 O6 PA1 X1000 LINK C2 KDO X1003 O4 KDO X1002 LINK C1 GLC X1006 O3 GMH X1005 LINK C1 GLA X1008 O6 GLC X1006 LINK C1 GLC X1007 O3 GLC X1006 LINK O5 KDO X1002 C1 GMH X1004 LINK C1 GMH X1005 O3 GMH X1004 PDB entry 1qff

45. E55 ERITORAN di-saccharide drug for the treatment of severe sepsis http://en.wikipedia.org/wiki/Eritoran

46.  Occurs on the outer membrane of gram-negative bacteria (e.g.: E. coli, Salmonella typhimurium)  Prime targets of antibodies  Some bacterial polysaccharides are toxic to humans Lipopolysaccharides

47. Bacterial Cell Walls The NAM-NAG polysaccharide is in turn cross- linked by small peptides  in Staphylococcus aureus, the cross link is a tetrapeptide  this tetrapeptide is unusual in that it contains two amino acids of the D-series, namely D-Ala and D-Gln  each tetrapeptide is cross linked to an adjacent tetrapeptide by a pentapeptide of five glycine units

48. Large polymers composed of alternating beta(1-4)- linked N-acetylglucosamine (GlcNAc) and N- acetylmuramic acid (MurNAc) residues, which are cross-linked by short peptide bridges. Lysine is commonly the third amino acid of the peptide moieties of PGN of Gram-positive bacteria while Gram-negative bacteria have a diaminopimelic acid (DAP) residue at this position. http://en.wikipedia.org/wiki/Peptidoglycan

49. N-Acetylglucosamine (NAG) N-Acetylmuramic acid (NAM) L-Ala D-Isoglutamate L-Lys D-Ala

50. Lysozyme Penicillin Bacterial Cell Walls The peptidoglycan of a bacterial cell wall

51. Gram-positive Cells In Gram-positive cells, peptidoglycan makes up as much as 90% of the thick, compact cell wall, which is the outermost structure. Gram-negative Cells The cell walls of Gram - bacteria are more chemically complex, thinner and less compact. Peptidoglycan makes up only 5-20% of the cell wall, and is not the outermost layer, but lies between the plasma membrane and an outer membrane.

52. The primary difference between the immunopathogenesis of Gram-positive and negative sepsis lies in their causative agents. In the case of Gram-negative bacteria, endotoxin (a lipopolysaccaride) has been identified as the causative agent. Endotoxin is absent in Gram-positive bacteria, instead the cell wall contains a thick layer of peptidoglycan. Lipoteichoic acids are embedded in the PGN layer and these bacterial cell wall components are capable of inducing the production of pro-inflammatory cytokines to induce various pathways causing sepsis. http://en.wikipedia.org/wiki/Sepsis Sepsis is a severe illness in which the bloodstream is overwhelmed by bacteria.

53. 9lyz BACTERIAL CELL WALL TRISACCHARIDE AMU NAG AMU AMU BETA-N-ACETYLMURAMIC ACID NAG N-ACETYL-D-GLUCOSAMINE Weird PDB Protein not deposited

54. 2aph MURAMYL PENTAPEPTIDE AMU ALA GMA LYS DAL DAL NH2 AMU BETA-N-ACETYLMURAMIC ACID GMA 4-AMIDO-4-CARBAMOYL-BUTYRIC ACID DAL D-ALANINE NH2 AMINO GROUP

55. Nature Reviews Drug Discovery, 9 308-324 (April 2010) Recommended Reading Definitions http://www.chem.qmul.ac.uk/iupac/misc/glycp.html

56. Look up the classes of glyco-chemistry listed here and report on their occurrance in the PDB and their binding, their natural source and uses TASKS 1.Simple Glycosides (e.g. 7CA ICARISID II is another flavonoid glycoside) 2.The antibiotic classes and any more members (e.g. IVM IVERMECTIN is an antiparasitic) 3.Lipopolysaccharides as drugs/metabolites 4.Other Carbohydrates as drugs and toxins (e.g. PXT PECTENOTOXIN-2)