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Ex-527 Inhibits Sirtuins by Exploiting Their Unique NAD+-dependent Deacetylation Mechanism

Ex-527 Inhibits Sirtuins by Exploiting Their Unique NAD+-dependent Deacetylation Mechanism

Melanie Gertz, Frank Fischer, Giang Thi Tuyet Nguyen, Mahadevan Lakshminarasimhan, Mike Schutkowski, Michael Weyand, Clemens Steegborn

Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):E2772-81.

PMID: 23840057

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP49843983-A	EX-527		49843-98-3	Price

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