Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide-Activated Sirtuin 7**
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Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide-Activated Sirtuin 7**. / Bolding, Julie E.; Nielsen, Alexander L.; Jensen, Iben; Hansen, Tobias N.; Ryberg, Line A.; Jameson, Samuel T.; Harris, Pernille; Peters, Günther H.J.; Denu, John M.; Rogers, Joseph M.; Olsen, Christian A.
In: Angewandte Chemie - International Edition, Vol. 62, No. 49, e202314597, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide-Activated Sirtuin 7**
AU - Bolding, Julie E.
AU - Nielsen, Alexander L.
AU - Jensen, Iben
AU - Hansen, Tobias N.
AU - Ryberg, Line A.
AU - Jameson, Samuel T.
AU - Harris, Pernille
AU - Peters, Günther H.J.
AU - Denu, John M.
AU - Rogers, Joseph M.
AU - Olsen, Christian A.
N1 - Publisher Copyright: © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
PY - 2023
Y1 - 2023
N2 - The sirtuins are NAD+-dependent lysine deacylases, comprising seven isoforms (SIRT1–7) in humans, which are involved in the regulation of a plethora of biological processes, including gene expression and metabolism. The sirtuins share a common hydrolytic mechanism but display preferences for different ϵ-N-acyllysine substrates. SIRT7 deacetylates targets in nuclei and nucleoli but remains one of the lesser studied of the seven isoforms, in part due to a lack of chemical tools to specifically probe SIRT7 activity. Here we expressed SIRT7 and, using small-angle X-ray scattering, reveal SIRT7 to be a monomeric enzyme with a low degree of globular flexibility in solution. We developed a fluorogenic assay for investigation of the substrate preferences of SIRT7 and to evaluate compounds that modulate its activity. We report several mechanism-based SIRT7 inhibitors as well as de novo cyclic peptide inhibitors selected from mRNA-display library screening that exhibit selectivity for SIRT7 over other sirtuin isoforms, stabilize SIRT7 in cells, and cause an increase in the acetylation of H3 K18.
AB - The sirtuins are NAD+-dependent lysine deacylases, comprising seven isoforms (SIRT1–7) in humans, which are involved in the regulation of a plethora of biological processes, including gene expression and metabolism. The sirtuins share a common hydrolytic mechanism but display preferences for different ϵ-N-acyllysine substrates. SIRT7 deacetylates targets in nuclei and nucleoli but remains one of the lesser studied of the seven isoforms, in part due to a lack of chemical tools to specifically probe SIRT7 activity. Here we expressed SIRT7 and, using small-angle X-ray scattering, reveal SIRT7 to be a monomeric enzyme with a low degree of globular flexibility in solution. We developed a fluorogenic assay for investigation of the substrate preferences of SIRT7 and to evaluate compounds that modulate its activity. We report several mechanism-based SIRT7 inhibitors as well as de novo cyclic peptide inhibitors selected from mRNA-display library screening that exhibit selectivity for SIRT7 over other sirtuin isoforms, stabilize SIRT7 in cells, and cause an increase in the acetylation of H3 K18.
KW - Epigenetics
KW - Histones
KW - Lysine acylation
KW - mRNA Display
KW - Posttranslational Modification
U2 - 10.1002/anie.202314597
DO - 10.1002/anie.202314597
M3 - Journal article
C2 - 37873919
AN - SCOPUS:85175817167
VL - 62
JO - Angewandte Chemie International Edition
JF - Angewandte Chemie International Edition
SN - 1433-7851
IS - 49
M1 - e202314597
ER -
ID: 373616802