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Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism.

Title data

Gertz, Melanie ; Fischer, Frank ; Nguyen, Giang Thi Tuyet ; Lakshminarasimhan, Mahadevan ; Schutkowski, Mike ; Weyand, Michael ; Steegborn, Clemens:
Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism.
In: Proceedings of the National Academy of Sciences of the United States of America. Vol. 110 (23 July 2013) Issue 30 . - E2772-E2781.
ISSN 1091-6490
DOI: https://doi.org/10.1073/pnas.1303628110

Abstract in another language

Sirtuins are protein deacetylases regulating metabolism and stress responses. The seven human Sirtuins (Sirt1-7) are attractive drug targets, but Sirtuin inhibition mechanisms are mostly unidentified. We report the molecular mechanism of Sirtuin inhibition by 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (Ex-527). Inhibitor binding to potently inhibited Sirt1 and Thermotoga maritima Sir2 and to moderately inhibited Sirt3 requires NAD(+), alone or together with acetylpeptide. Crystal structures of several Sirtuin inhibitor complexes show that Ex-527 occupies the nicotinamide site and a neighboring pocket and contacts the ribose of NAD(+) or of the coproduct 2'-O-acetyl-ADP ribose. Complex structures with native alkylimidate and thio-analog support its catalytic relevance and show, together with biochemical assays, that only the coproduct complex is relevant for inhibition by Ex-527, which stabilizes the closed enzyme conformation preventing product release. Ex-527 inhibition thus exploits Sirtuin catalysis, and kinetic isoform differences explain its selectivity. Our results provide insights in Sirtuin catalysis and inhibition with important implications for drug development.

Further data

Item Type: Article in a journal
Refereed: Yes
Additional notes: PubMed-ID: 16905097
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: Yes
DDC Subjects: 500 Science > 540 Chemistry
Date Deposited: 20 Apr 2015 12:25
Last Modified: 18 Apr 2018 11:23
URI: https://eref.uni-bayreuth.de/id/eprint/10422