Back to Search Start Over

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

Authors :
Mahadevan Lakshminarasimhan
Clemens Steegborn
Frank Fischer
Melanie Gertz
Mike Schutkowski
Michael Weyand
Giang Thi Tuyet Nguyen
Source :
Proceedings of the National Academy of Sciences. 110
Publication Year :
2013
Publisher :
Proceedings of the National Academy of Sciences, 2013.

Abstract

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.

Details

ISSN :
10916490 and 00278424
Volume :
110
Database :
OpenAIRE
Journal :
Proceedings of the National Academy of Sciences
Accession number :
edsair.doi.dedup.....4ca8fba4823d93c095931703cb5c984a
Full Text :
https://doi.org/10.1073/pnas.1303628110