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 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.
Duke Scholars
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Related Subject Headings
- Zebrafish Proteins
- Zebrafish
- Substrate Specificity
- Structure-Activity Relationship
- Sirtuins
- Organic Chemistry
- Molecular Structure
- Kinetics
- Humans
- Histone Deacetylase Inhibitors
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Zebrafish Proteins
- Zebrafish
- Substrate Specificity
- Structure-Activity Relationship
- Sirtuins
- Organic Chemistry
- Molecular Structure
- Kinetics
- Humans
- Histone Deacetylase Inhibitors