Angewandte Chemie - International Edition
Angewandte Chemie - International Edition
5 years ago

Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight

Andreas S. Madsen, Clemens Steegborn, Martin Pannek, Matthew D Hirshey, Martin Fontenas, Marina Auth, Christian Adam Olsen, Dhaval Bhatt, Kathrin R. Troelsen, Nima Rajabi
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 sirtuins. This is important information when applying inhibitors to probe mechanisms in biology.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201709050

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