70144-58-0Relevant academic research and scientific papers
Binding of the Bacterial Adhesin FimH to Its Natural, Multivalent High-Mannose Type Glycan Targets
Sauer, Maximilian M.,Jakob, Roman P.,Luber, Thomas,Canonica, Fabia,Navarra, Giulio,Ernst, Beat,Unverzagt, Carlo,Maier, Timm,Glockshuber, Rudi
, p. 936 - 944 (2019/01/11)
Multivalent carbohydrate-lectin interactions at host-pathogen interfaces play a crucial role in the establishment of infections. Although competitive antagonists that prevent pathogen adhesion are promising antimicrobial drugs, the molecular mechanisms underlying these complex adhesion processes are still poorly understood. Here, we characterize the interactions between the fimbrial adhesin FimH from uropathogenic Escherichia coli strains and its natural high-mannose type N-glycan binding epitopes on uroepithelial glycoproteins. Crystal structures and a detailed kinetic characterization of ligand-binding and dissociation revealed that the binding pocket of FimH evolved such that it recognizes the terminal α(1-2)-, α(1-3)-, and α(1-6)-linked mannosides of natural high-mannose type N-glycans with similar affinity. We demonstrate that the 2000-fold higher affinity of the domain-separated state of FimH compared to its domain-associated state is ligand-independent and consistent with a thermodynamic cycle in which ligand-binding shifts the association equilibrium between the FimH lectin and the FimH pilin domain. Moreover, we show that a single N-glycan can bind up to three molecules of FimH, albeit with negative cooperativity, so that a molar excess of accessible N-glycans over FimH on the cell surface favors monovalent FimH binding. Our data provide pivotal insights into the adhesion properties of uropathogenic Escherichia coli strains to their target receptors and a solid basis for the development of effective FimH antagonists.
Regioselective glycosylation reactions based on computational predictions
Kalikanda, Jane,Li, Zhitao
experimental part, p. 1550 - 1553 (2010/06/13)
Regioselectivity is a major issue in glycosylation reactions. Better understanding of regioselectivity of acceptors can greatly facilitate and simplify the syntheses of oligosaccharides. The reactivity of diol acceptors is often affected by stereochemistry and protecting groups, which make prediction the regioselectivity of diol acceptors extremely difficult. Quantum mechanic methods were used to study the relationship between protecting groups and reactivity of diol acceptor and a correlation between Fukui function and regioselectivity is established through series of glycosylation reactions.
Synthesis of a αMan(1→3)αMan(1→2)αMan glycocluster presented on a β-cyclodextrin scaffold
Carpenter, Clare,Nepogodiev, Sergey A.
, p. 3286 - 3296 (2007/10/03)
Application of 6-thio-α- and β-cyclodextrins as the core component for the construction of multivalent carbohydrate structures is described. The method employed for the attachment of monomeric glycosides to a cyclodextrin core is based on the efficient nu
Synthesis of a 3,4-di-O-substituted heptose structure: A partial oligosaccharide expressed in Neisserial lipooligosaccharide
Kubo, Hiroyuki,Ishii, Kazuyuki,Koshino, Hiroyuki,Toubetto, Kenji,Naruchi, Kentarou,Yamasaki, Ryohei
, p. 1202 - 1213 (2007/10/03)
We have synthesized a tetrasaccharide containing a 3,4-di-branched L-glycero-D-manno-heptose (Hep), β-lactosyl-(1→4)-[L-α-D-Hep- (1→3)]-L-α-D-Hep 19, by using a mannose (Man) derivative as an acceptor. Prior to the construction of the branched Hep, we confirmed that the 3,4-dibranched Man structure could be synthesized using a 3-branched Man 6 as an acceptor. Glycosylation of the acceptor 6 using hepta-O-acetyl-α-lactosyl trichloroacetimidate (7) gave the desired 3,4-dibranched structure, β-lactosyl-(1→4)-[α-Man-(1→3)]-α-Man 8. As expected, β-lactosyl-(1→4)-[L-α-D-Hep-(1→3)]-α-D-Man 14 was also obtained by glycosylating the 4-OH acceptor 13 with 7 in a similar manner. The Man residue of 14 was converted into the Hep unit by Swern oxidation, Grignard reaction, and oxidative cleavage followed by reduction. Thus, we constructed the 3,4-dibranched Hep structure 19 by using the 3-branched Man 13 as an acceptor. The current results demonstrate that the gauche orientation of the O-3 and O-4 units of the Man configuration does not prevent the formation of the 3,4-di-O-substituted structure. This approach should provide an alternative method to synthesize the 3,4-dibranched Hep structure expressed in LOS produced by pathogenic Gram-negative bacteria such as the Neisserial and Haemophilus species. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
