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Angw-oct17-Inhibitors-Human Sirtuin 5 Deacylase

Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase

October 23, 2017

Keywords: enzyme inhibitors • sirtuins • posttranslational modifications • deacylases • drug discovery

Angew. Chem. Int. Ed.; 2017,
Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase:
Structure–Activity Relationship, Biostructural, and Kinetic Insight
Nima Rajabi, Marina Auth, Kathrin R. Troelsen, Martin Pannek, Dhaval P. Bhatt, Martin Fontenas, Prof. Dr. Matthew D. Hirschey, Prof. Dr. Clemens Steegborn, Prof. Dr. Andreas S. Madsen, Prof. Dr. Christian A. Olsen


The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more “drug-like” properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology

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