Objectif Gleeman chains on the surface of mammalian cells are responsible for a variety of cell-cell recognition reactions. It is well established that a failure or disturbance of the biosynthesis of membrane associated carbohydrates leads to severe pathological conditions. More recently, it has been shown that the increased occurrence of distinct oligosaccharide motifs is responsible for the metastasis potential of particular tumour types. The increased biosynthesis of oligosaccharide epitomes is due an elevated expression of human glycosyltransferases. Therefore, the selective inhibition of human glycosyltransferases is an important and challenging topic that has the potential to pave the way for novel concepts in anti-tumour therapy. The ABO blood group galactosyltransferase and the human sialyltransferase hST3-Gal-lll where chosen as targets because of their biological significance. Both enzymes will be subjected to NMR studies with substrates and substrate analogues. With saturation transfer difference (STD) NMR techniques the binding epitomes of donor- and acceptor-substrates will be determined at atomic resolution. Transfer NOE experiments subsequently deliver information about the bioactive conformations of the substrates. Uniformly and specifically isotope enriched (15N, 13C, and 2H) ABO galactosyltransferase is produced in E.coli in very good yields. TROSY-type NMR experiments will allow to define the binding pocket of the enzyme. In conjunction with the knowledge about the binding epitomes of the legends this will yield additional valuable restraints for the design of potential glycosyltransferase inhibitors. The NMR results will be used to design small molecule inhibitors that will be synthesized, and in turn will also be subjected to NMR binding studies. The NMR studies will be complemented by additional techniques such as Biscoe experiments. It is envisioned that this iterative process leads to potent glycosyltransferase inhibitors. Champ scientifique natural sciencesmathematicspure mathematicsmathematical analysisnatural sciencesphysical sciencesopticsspectroscopyabsorption spectroscopynatural sciencesbiological sciencesbiochemistrybiomoleculescarbohydratesnatural scienceschemical sciencesorganic chemistryaminesnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Mots‑clés Human Glycosyltransferases Molecular Recognition NMR Spectroscopy Surface Plasmon Resonance Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Thème(s) MOBILITY-2.1 - Marie Curie Intra-European Fellowships (EIF) Appel à propositions FP6-2002-MOBILITY-5 Voir d’autres projets de cet appel Régime de financement EIF - Marie Curie actions-Intra-European Fellowships Coordinateur UNIVERSITAET LUEBECK Contribution de l’UE Aucune donnée Adresse Ratzeburger Allee 160 LUEBECK Allemagne Voir sur la carte Coût total Aucune donnée
