title: 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.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs Universität , Albertstrasse 25, 79104 Freiburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Maurer
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs Universität , Albertstrasse 25, 79104 Freiburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Rumpf
authors.affiliation: Department of Pharmaceutical Chemistry, Martin-Luther Universität Halle-Wittenberg , Universitätsplatz 7, 06120 Halle/Saale, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Scharfe
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs Universität , Albertstrasse 25, 79104 Freiburg, Germany.
authors.forename: Diana A
authors.initials: DA
authors.lastname: Stolfa
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs Universität , Albertstrasse 25, 79104 Freiburg, Germany.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Schmitt
authors.affiliation: Gladstone Institute of Virology and Immunology , 1650 Owens Street, San Francisco, California 94158, United States.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: He
authors.affiliation: Gladstone Institute of Virology and Immunology , 1650 Owens Street, San Francisco, California 94158, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.affiliation: Department of Pharmaceutical Chemistry, Martin-Luther Universität Halle-Wittenberg , Universitätsplatz 7, 06120 Halle/Saale, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs Universität , Albertstrasse 25, 79104 Freiburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
keywords: AMC assay; Sirt5; desuccinylation; sirtinol; sirtuin