Inhibition of a bacterial <Emphasis Type="Italic">O</Emphasis>-GlcNAcase homologue by lactone and lactam derivatives: structural,kinetic and thermodynamic analyses |
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Authors: | Yuan He Abigail K Bubb Keith A Stubbs Tracey M Gloster Gideon J Davies |
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Institution: | (1) York Structural Biology Laboratory, Department of Chemistry, The University of York, York, YO10 5DD, UK;(2) Present address: Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada;(3) Present address: School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia (M310), 35 Stirling Highway, Crawley, WA, 6009, Australia; |
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Abstract: | The dynamic, intracellular, O-GlcNAc modification is of continuing interest and one whose study through targeted “chemical genetics” approaches is set
to increase. Of particular importance is the inhibition of the O-GlcNAc hydrolase, O-GlcNAcase (OGA), since this provides a route to elevate cellular O-GlcNAc levels, and subsequent phenotypic evaluation. Such a small molecule approach complements other methods and potentially
avoids changes in protein–protein interactions that manifest themselves in molecular biological approaches to O-GlcNAc transferase knockout or over-expression. Here we describe the kinetic, thermodynamic and three-dimensional structural
analysis of a bacterial OGA analogue from Bacteroides thetaiotaomicron, BtGH84, in complex with a lactone oxime (LOGNAc) and a lactam form of N-acetylglucosamine and compare their binding signatures with that of the more potent inhibitor O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino N-phenyl carbamate (PUGNAc). We show that both LOGNAc and the N-acetyl gluconolactam are significantly poorer inhibitors than PUGNAc, which may reflect poorer mimicry of transition state
geometry and steric clashes with the enzyme upon binding; drawbacks that the phenyl carbamate adornment of PUGNAc helps mitigate.
Implications for the design of future generations of inhibitors are discussed. |
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