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


  • eng

Conference Location

  • Germany