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Ex-527 inhibits Sirtuins by exploiting their unique NAD + -dependent deacetylation mechanism
- 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.
- Subjects :
- Models, Molecular
chemistry.chemical_classification
Multidisciplinary
SIRT3
Nicotinamide
Carbazoles
Acetylation
Stereoisomerism
Biology
NAD
biology.organism_classification
chemistry.chemical_compound
Enzyme
PNAS Plus
chemistry
Biochemistry
Thermotoga maritima
Ribose
Sirtuin
biology.protein
Sirtuins
NAD+ kinase
Subjects
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