23202-66-6Relevant articles and documents
Rational Design of Glycomimetic Compounds Targeting the Saccharomyces cerevisiae Transglycosylase Gas2
Delso, Ignacio,Valero-González, Jessika,Marca, Eduardo,Tejero, Tomás,Hurtado-Guerrero, Ramón,Merino, Pedro
, p. 163 - 170 (2016)
The transglycosylase Saccharomyces cerevisiae Gas2 (ScGas2) belongs to a large family of enzymes that are key players in yeast cell wall remodeling. Despite its biologic importance, no studies on the synthesis of substrate-based compounds as potential inhibitors have been reported. We have synthesized a series of docking-guided glycomimetics that were evaluated by fluorescence spectroscopy and saturation-transfer difference (STD) NMR experiments, revealing that a minimum of three glucose units linked via a β-(1,3) linkage are required for achieving molecular recognition at the binding donor site. The binding mode of our compounds is further supported by STD-NMR experiments using the active site-mutants Y107Q and Y244Q. Our results are important for both understanding of ScGas2-substrate interactions and setting up the basis for future design of glycomimetics as new antifungal agents.
Orthogonal Active-Site Labels for Mixed-Linkage endo-β-Glucanases
Jain, Namrata,Tamura, Kazune,Déjean, Guillaume,Van Petegem, Filip,Brumer, Harry
, p. 1968 - 1984 (2021/05/26)
Small molecule irreversible inhibitors are valuable tools for determining catalytically important active-site residues and revealing key details of the specificity, structure, and function of glycoside hydrolases (GHs). β-glucans that contain backbone β(1,3) linkages are widespread in nature, e.g., mixed-linkage β(1,3)/β(1,4)-glucans in the cell walls of higher plants and β(1,3)glucans in yeasts and algae. Commensurate with this ubiquity, a large diversity of mixed-linkage endoglucanases (MLGases, EC 3.2.1.73) and endo-β(1,3)-glucanases (laminarinases, EC 3.2.1.39 and EC 3.2.1.6) have evolved to specifically hydrolyze these polysaccharides, respectively, in environmental niches including the human gut. To facilitate biochemical and structural analysis of these GHs, with a focus on MLGases, we present here the facile chemo-enzymatic synthesis of a library of active-site-directed enzyme inhibitors based on mixed-linkage oligosaccharide scaffolds and N-bromoacetylglycosylamine or 2-fluoro-2-deoxyglycoside warheads. The effectiveness and irreversibility of these inhibitors were tested with exemplar MLGases and an endo-β(1,3)-glucanase. Notably, determination of inhibitor-bound crystal structures of a human-gut microbial MLGase from Glycoside Hydrolase Family 16 revealed.
Stereoselective Ethynylation and Propargylation of Chiral Cyclic Nitrones: Application to the Synthesis of Glycomimetics
García-Vi?uales, Sara,Delso, Ignacio,Merino, Pedro,Tejero, Tomás
, p. 3339 - 3351 (2016/09/09)
Ethynylation and propargylation of chiral nonracemic polyhydroxylated cyclic nitrones with Grignard reagents are efficient methods for preparing building blocks containing an alkyne moiety to be used in copper-catalyzed azide alkyne cycloaddition click chemistry. Whereas ethynylation takes place with excellent diastereoselectivity, propargylation afforded mixtures of diastereomers in some cases. The use of (trimethylsilyl)propargyl bromide as precursor of the Grignard reagent is necessary to avoid the formation of undesired allene derivatives. DFT calculations explain, within the experimental error, the observed behavior. Cycloaddition of the obtained pyrrolidinyl alkynes with sugar azides derived from β-(1,3)-glucans provides glycomimetics suitable to be used against fungal transglycosylases.
