2. Academic Validation
  3. Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight

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

  • Angew Chem Int Ed Engl. 2017 Nov 20;56(47):14836-14841. doi: 10.1002/anie.201709050.
Nima Rajabi 1,  Marina Auth 1,  Kathrin R Troelsen 1,  Martin Pannek 2,  Dhaval P Bhatt 3,  Martin Fontenas 1,  Matthew D Hirschey 3,  Clemens Steegborn 2,  Andreas S Madsen 1,  Christian A Olsen 1
Affiliations

Affiliations

  • 1 Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
  • 2 Universität Bayreuth, Lehrstuhl Biochemie und Forschungszentrum für Biomakromoleküle, Universitätsstrasse 30, 95447, Bayreuth, Germany.
  • 3 Duke University Medical Center, Sarah W. Stedman Nutrition and Metabolism Center, 4321 Medical Park Drive, Durham, NC, 27704, USA.
PMID: 29044784 DOI: 10.1002/anie.201709050
Abstract

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.

Keywords

deacylases; drug discovery; enzyme inhibitors; posttranslational modifications; sirtuins.

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