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

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Nima Rajabi, Marina Auth, Kathrin Rentzius Troelsen, Martin Pannek, Dhaval Bhatt, Martin Fontenas, Matthew Hirschey, Clemens Steegborn, Andreas Stahl Madsen, Christian Adam 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 sirtuins. This is important information when applying inhibitors to probe mechanisms in biology.
OriginalsprogEngelsk
TidsskriftAngewandte Chemie, Int. Ed.
Vol/bind56
Tidsskriftsnummer47
Sider (fra-til)14836-14841
ISSN1433-7851
DOI
StatusUdgivet - 20 nov. 2017

ID: 184635999