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.
| Original language | English |
|---|---|
| Journal | Journal of Medicinal Chemistry |
| Volume | 59 |
| Issue number | 3 |
| Pages (from-to) | 1021-31 |
| Number of pages | 11 |
| ISSN | 0022-2623 |
| DOIs | |
| Publication status | Published - 11 Feb 2016 |
Keywords
- Acetamides
- Dose-Response Relationship, Drug
- Drug Evaluation, Preclinical
- Enzyme Inhibitors
- Fluorescent Dyes
- Humans
- Lysine
- Models, Molecular
- Molecular Structure
- Sirtuin 2
- Structure-Activity Relationship
- Substrate Specificity
- Suramin
- Thiazoles
- Journal Article
- Research Support, Non-U.S. Gov't