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

Nima Rajabi; Marina Auth; Kathrin Rentzius Troelsen; Martin Pannek; Dhaval Bhatt; Martin Fontenas; Matthew Hirschey; Clemens Steegborn; Andreas Stahl Madsen; Christian Adam Olsen

doi:10.1002/anie.201709050

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

Nima Rajabi, Marina Auth, Kathrin Rentzius Troelsen, Martin Pannek, Dhaval Bhatt, Martin Fontenas, Matthew Hirschey, Clemens Steegborn, Andreas Stahl Madsen, Christian Adam Olsen

22 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Angewandte Chemie, Int. Ed.
Vol/bind	56
Udgave nummer	47
Sider (fra-til)	14836-14841
ISSN	1433-7851
DOI	https://doi.org/10.1002/anie.201709050
Status	Udgivet - 20 nov. 2017

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10.1002/anie.201709050

http://europepmc.org/articles/pmc5814306?pdf=renderLicens: Ikke-specificeret

Citationsformater

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AU - Rajabi, Nima

AU - Auth, Marina

AU - Troelsen, Kathrin Rentzius

AU - Pannek, Martin

AU - Bhatt, Dhaval

AU - Fontenas, Martin

AU - Hirschey, Matthew

AU - Steegborn, Clemens

AU - Madsen, Andreas Stahl

AU - Olsen, Christian Adam

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AB - 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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DO - 10.1002/anie.201709050

M3 - Journal article

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JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

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

Abstract

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