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Mechanism‐Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure–Activity Relationship, Biostructural, and Kinetic Insight
Author(s) -
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.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201709050
Subject(s) - sirtuin , mechanism (biology) , zebrafish , chemistry , rationalization (economics) , enzyme , drug discovery , small molecule , computational biology , enzyme activator , biochemistry , biology , nad+ kinase , gene , philosophy , epistemology
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.