Inhibitors of the NAD(+)-Dependent Protein Desuccinylase and Demalonylase Sirt5.

Abstract

NAD(+)-dependent histone deacetylases (sirtuins) play important roles in epigenetic regulation but also through nonhistone substrates for other key cellular events and have been linked to the pathogenesis of cancer, neurodegeneration, and metabolic diseases. The subtype Sirt5 has been shown recently to act as a desuccinylating and demalonylating enzyme. We have established an assay for biochemical testing of Sirt5 using a small labeled succinylated lysine derivative. We present a comparative study on the profiling of several established sirtuin inhibitors on Sirt1-3 as well as Sirt5 and also present initial results on a screening for new compounds that block Sirt5. Thiobarbiturates were identified as new Sirt5 inhibitors in the low micromolar range, which are selective over Sirt3 that can be found in the same cell compartment as Sirt5.

• Authors: Benjamin Maurer, Tobias Rumpf, Michael Scharfe, Diana A Stolfa, Martin L Schmitt, Wenjuan He, Eric Verdin, Wolfgang Sippl, Manfred Jung
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 3 Issue 12 Pg. 1050-3 (Dec 13 2012) ISSN: 1948-5875 [Print] United States
• PMID: 24900427 (Publication Type: Journal Article)