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Inhibition of a bacterial O-GlcNAcase homologue by lactone and lactam derivatives: structural, kinetic and thermodynamic analyses

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JournalAMINO ACIDS
DatePublished - Mar 2011
Issue number3
Volume40
Number of pages11
Pages (from-to)829-839
Original languageEnglish

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.

    Research areas

  • Carbohydrate, Enzyme, X-ray structure, O-GlcNAc, Diabetes, Neurodegeneration, BETA-N-ACETYLGLUCOSAMINIDASE, TRANSITION-STATE MIMICS, INSULIN-RESISTANCE, ALZHEIMERS-DISEASE, SELECTIVE-INHIBITION, 3T3-L1 ADIPOCYTES, D-GLUCOSAMINIDASE, LINKED GLCNAC, MECHANISM, GLYCOSYLATION

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