A Continuous, Fluorogenic Sirtuin 2 Deacylase Assay: Substrate Screening and Inhibitor Evaluation

Journal of Medicinal Chemistry
Iacopo GalleanoChristian A Olsen

Abstract

Sirtuins are important regulators of lysine acylation, which is implicated in cellular metabolism and transcriptional control. This makes the sirtuin class of enzymes interesting targets for development of small molecule probes with pharmaceutical potential. To achieve detailed profiling and kinetic insight regarding sirtuin inhibitors, it is important to have access to efficient assays. In this work, we report readily synthesized fluorogenic substrates enabling enzyme-economical evaluation of SIRT2 inhibitors in a continuous assay format as well as evaluation of the properties of SIRT2 as a long chain deacylase enzyme. Novel enzymatic activities of SIRT2 were thus established in vitro, which warrant further investigation, and two known inhibitors, suramin and SirReal2, were profiled against substrates containing ε-N-acyllysine modifications of varying length.

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Citations

Jan 18, 2017·Medicinal Research Reviews·Matthias SchiedelManfred Jung
Jun 23, 2018·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Dina RobaaManfred Jung
May 5, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hui WenHuaqing Cui
Jan 27, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Di ChenWeiping Zheng
Apr 25, 2018·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Sören SwyterManfred Jung
Jul 31, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lijiao WangLingling Yang
Feb 11, 2016·The Journal of Biological Chemistry·Andreas S MadsenChristian A Olsen
Apr 13, 2021·The Journal of Organic Chemistry·Mizzanoor RahamanM Mahmun Hossain
Oct 17, 2020·ACS Medicinal Chemistry Letters·Nima RajabiChristian A Olsen
Oct 7, 2021·Chemical Communications : Chem Comm· RoopaNaresh Kumar

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