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

Title data

Rajabi, Nima ; Auth, Marina ; Troelsen, Kathrin R. ; Pannek, Martin ; Bhatt, Dhaval ; Fontenas, Martin ; Hirshey, Matthew D. ; Steegborn, Clemens ; Madsen, Andreas S. ; Olsen, Christian Adam:
Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase : Structure-Activity Relationship, Biostructural, and Kinetic Insight.
In: Angewandte Chemie International Edition. (17 October 2017) .
ISSN 1521-3773
DOI: https://doi.org/10.1002/anie.201709050

Abstract in another language

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 sirtuins. This is important information when applying inhibitors to probe mechanisms in biology.

Further data

Item Type: Article in a journal
Refereed: Yes
Additional notes: Accepted, unedited article published online and citable. The final edited and typeset version of record will appear in future.
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry
Result of work at the UBT: No
DDC Subjects: 500 Science > 540 Chemistry
Date Deposited: 20 Oct 2017 09:43
Last Modified: 20 Oct 2017 09:43
URI: https://eref.uni-bayreuth.de/id/eprint/40087