Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide-Activated Sirtuin 7**
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | e202314597 |
| Tidsskrift | Angewandte Chemie - International Edition |
| Vol/bind | 62 |
| Udgave nummer | 49 |
| ISSN | 1433-7851 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
We thank Drs. Peter Fristrup and Ana Rita Colaço (PhD thesis, DTU Chemistry 2017) for early homology modeling work on SIRT7 that is not included in the present manuscript. We thank Jose Moran and Slava Kuznetsov (Denu laboratory) for nucleosome preparations and technical insight. We acknowledge DESY (Hamburg, Germany), a member of the Helmholtz Association HGF, for providing beam time for the SAXS experiments and provision of experimental facilities; the data were collected at PETRA III beamline P12 operated by EMBL Hamburg. Beamtime was allocated for proposal SAXS‐734. We thank the NIH (R35GM149279; J.M.D.), the Novo Nordisk Foundation (NNF19OC0054441; J.M.R.), and the Independent Research Fund Denmark‐Medical Sciences (0134‐00435B; C.A.O.) for financial support. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement number: 725172‐; C.A.O.). SIRFUNCT
Publisher Copyright:
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
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