A Continuous, Fluorogenic Sirtuin 2 Deacylase Assay: Substrate Screening and Inhibitor Evaluation
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A Continuous, Fluorogenic Sirtuin 2 Deacylase Assay : Substrate Screening and Inhibitor Evaluation. / Galleano, Iacopo; Schiedel, Matthias; Jung, Manfred; Madsen, Andreas S; Olsen, Christian A.
I: Journal of Medicinal Chemistry, Bind 59, Nr. 3, 11.02.2016, s. 1021-31.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - A Continuous, Fluorogenic Sirtuin 2 Deacylase Assay
T2 - Substrate Screening and Inhibitor Evaluation
AU - Galleano, Iacopo
AU - Schiedel, Matthias
AU - Jung, Manfred
AU - Madsen, Andreas S
AU - Olsen, Christian A
PY - 2016/2/11
Y1 - 2016/2/11
N2 - 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.
AB - 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.
KW - Acetamides
KW - Dose-Response Relationship, Drug
KW - Drug Evaluation, Preclinical
KW - Enzyme Inhibitors
KW - Fluorescent Dyes
KW - Humans
KW - Lysine
KW - Models, Molecular
KW - Molecular Structure
KW - Sirtuin 2
KW - Structure-Activity Relationship
KW - Substrate Specificity
KW - Suramin
KW - Thiazoles
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1021/acs.jmedchem.5b01532
DO - 10.1021/acs.jmedchem.5b01532
M3 - Journal article
C2 - 26788965
VL - 59
SP - 1021
EP - 1031
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 3
ER -
ID: 169443793