Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Rajabi, N; Auth, M; Troelsen, KR; Pannek, M; Bhatt, DP; Fontenas, M; Hirschey, MD; Steegborn, C; Madsen, AS; Olsen, CA
Published Date
- November 20, 2017
Published In
Volume / Issue
- 56 / 47
Start / End Page
- 14836 - 14841
PubMed ID
- 29044784
Pubmed Central ID
- PMC5814306
Electronic International Standard Serial Number (EISSN)
- 1521-3773
Digital Object Identifier (DOI)
- 10.1002/anie.201709050
Language
- eng
Conference Location
- Germany