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Glycoconjugates

Glyco-Chemistry and the PDB. Glycoconjugates. ( excluding Glycoproteins). CELLULOSE Fragments in PDB. ABL 5-amino-5-deoxy-cellobiono-1,5-lactam di-saccharide CBI CELLOBIOSE di-saccharide CE5 CELLOPENTAOSE penta-saccharide CE6 CELLOHEXAOSE hexa-saccharide

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Glycoconjugates

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

  2. CELLULOSE Fragments in PDB 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 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 CTO Umbelliferone can be used as a fluorescence dye http://en.wikipedia.org/wiki/Umbelliferone GUM

  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. Glycoproteins: 2 types(?) Proteoglycans have not been considered as glycoproteins because their carbohydrate seemed to differ so greatly 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 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

  7. GAG Glycosaminoglycan http://en.wikipedia.org/wiki/Glycosaminoglycan

  8. Simple Glycoconjugates: Glycosides are widely distributed in plants http://en.wikipedia.org/wiki/Glycoside The most important glycosides: • 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.

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

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

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

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

  13. Glycosaminoglycans

  14. Proteoglycans

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

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

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

  18. Heparin • 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. http://en.wikipedia.org/wiki/Heparin

  19. A portion of the structure of heparin 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) 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

  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. Oligosaccharides as drugs Antibiotics Polyketide – Antibiotics Glycopeptide antibiotic Aminoglycoside Anthracycline Glycosidic antibiotics Calichemicins and Esperamicins Aminoglycoside antibiotics

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

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

  25. polyketide macrolactams 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

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

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

  28. Aminoglycoside Anthracycline Antineoplastic/Antibiotic 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 http://en.wikipedia.org/wiki/Daunorubicin http://en.wikipedia.org/wiki/Anthracycline

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

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

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

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

  35. Calichemicins 2pik Enediyne antibiotic DNA minor groove binder

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

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

  38. AO3 ALLOSAMIDIN di-saccharide INSECTICIDE 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.

  39. type 2 diabetes mellitus 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

  40. Acarbose is an anti-diabetic drug used to treat type 2 diabetes mellitus alpha-amylase inhibitor 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 http://en.wikipedia.org/wiki/Acarbose

  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. Group 3 Any thing that looks vaguely like a Lipopolysaccharide 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. Lipopolysaccharides • 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

  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. http://en.wikipedia.org/wiki/Peptidoglycan 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.

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

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

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