Abstract
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.
Keywords:
STD-NMR; carbohydrates; docking; glycomimetics; transglycosylases.
© 2015 John Wiley & Sons A/S.
Publication types
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Editorial
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Research Support, Non-U.S. Gov't
MeSH terms
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Antifungal Agents / chemical synthesis*
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Antifungal Agents / metabolism
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Binding Sites
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Biomimetic Materials / chemical synthesis*
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Biomimetic Materials / chemistry
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Biomimetic Materials / metabolism
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Drug Design
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Glucose / chemistry*
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Glycoside Hydrolases / chemistry
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Glycoside Hydrolases / genetics
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Glycoside Hydrolases / metabolism*
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Molecular Docking Simulation
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Multienzyme Complexes / chemistry
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Multienzyme Complexes / genetics
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Multienzyme Complexes / metabolism*
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Mutagenesis, Site-Directed
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Nuclear Magnetic Resonance, Biomolecular
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Protein Structure, Tertiary
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Saccharomyces cerevisiae / enzymology*
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Saccharomyces cerevisiae Proteins / chemistry
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism*
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Spectrometry, Fluorescence
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Transferases / chemistry
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Transferases / genetics
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Transferases / metabolism*
Substances
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Antifungal Agents
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Multienzyme Complexes
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Saccharomyces cerevisiae Proteins
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transglycosidase enzyme system
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Transferases
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Glycoside Hydrolases
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Glucose