Chemical tools for unraveling the substrate specificity of the lysine deacylase enzymes

Andreas Stahl Madsen, Christian Adam Olsen

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Abstract

The lysine deacylase (KDAC) enzymes catalyze hydrolytic removal of acyl functionalities from theε-amino group of lysine residues ina variety of proteins including histones, and KDAC-mediated deacetylation of proteins has been established as a key epigeneticandmetabolic regulator. Recent studies have highlighted lysine acetylation as a general post-translational modification (PTM), andagrowing list of non-histone proteins has been identified as substrates for the KDACs, thereby extending their potential impactoncellular function. Furthermore, other acyl groups (e.g., crotonyl, malonyl, succinyl, glutaryl, myristoyl and 3-phosphoglyceroyl) havebeen identified as lysine PTMs, and both zinc- and NAD+-dependent KDACs have demonstrated capability to remove suchmodifications. These findings suggest that KDACs with impaired deacetylase activity might in fact be functional deacylases catalyzinghydrolysis of other acylamides. To address these interesting observations, we have synthesized a library of substrates containing different peptide scaffolds functionalized with a number of N - ε -acyl moieties. Library synthesis and its evaluation against a panel of human KDACs including zinc-dependent HDACs 1–11 as well as NAD + -dependent sirtuins (SIRT1–7) will be discussed.
Original languageEnglish
Publication date2014
Publication statusPublished - 2014
Event248th American Chemical Society National Meeting & Exposition: Chemistry and Global Stewardship - San Francisco, CA, United States
Duration: 10 Aug 201414 Aug 2014

Conference

Conference248th American Chemical Society National Meeting & Exposition
CountryUnited States
CitySan Francisco, CA
Period10/08/201414/08/2014

Bibliographical note

Tuesday, August 12, 2014 05:30 PM
Current Topics in Biological Chemistry (05:30 PM - 08:00 PM)
Location: San Francisco Marriott Marquis
Room: Golden Gate Section A/B

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