Mechanism‐Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure–Activity Relationship, Biostructural, and Kinetic Insight

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 da...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2017-11, Vol.56 (47), p.14836-14841
Main Authors: Rajabi, Nima, Auth, Marina, Troelsen, Kathrin R., Pannek, Martin, Bhatt, Dhaval P., Fontenas, Martin, Hirschey, Matthew D., Steegborn, Clemens, Madsen, Andreas S., Olsen, Christian A.
Format: Article
Language:English
Subjects:
Animals
Binding
Crystal structure
Crystallography, X-Ray
deacylases
Drug Discovery
enzyme inhibitors
Enzyme kinetics
Histone Deacetylase Inhibitors - chemistry
Histone Deacetylase Inhibitors - pharmacology
Humans
Inhibition
Inhibitors
Kinetics
Molecular Structure
Optimization
posttranslational modifications
sirtuins
Sirtuins - antagonists & inhibitors
Structure-Activity Relationship
Substrate Specificity
Zebrafish
Zebrafish Proteins - antagonists & inhibitors
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Summary: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. SAR studies of mechanism‐based inhibitors, combined with structural insight from X‐ray co‐crystal structures, provide potent inhibitors of the sirtuin 5 hydrolase. Kinetic investigations furthermore reveal unprecedented slow, tight‐binding behavior of several compounds.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201709050