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Suenkel, Benjamin ; Valente, Sergio ; Zwergel, Clemens ; Weiss, Sandra ; Di Bello, Elisabetta ; Fioravanti, Rossella ; Aventaggiato, Michele ; Amorim, João A. ; Garg, Neha ; Kumar, Surinder ; Lombard, David B. ; Hu, Tuo ; Singh, Pankaj K. ; Tafani, Marco ; Palmeira, Carlos M. ; Sinclair, David ; Mai, Antonello ; Steegborn, Clemens:
Potent and Specific Activators for Mitochondrial Sirtuins Sirt3 and Sirt5.
In: Journal of Medicinal Chemistry.
Bd. 65
(2022)
Heft 20
.
- S. 14015-14031.
ISSN 1520-4804
DOI: https://doi.org/10.1021/acs.jmedchem.2c01215
Abstract
Sirtuins are NAD+-dependent protein deacylases involved in metabolic regulation and aging-related diseases. Specific activators for seven human Sirtuin isoforms would be important chemical tools and potential therapeutic drugs. Activators have been described for Sirt1 and act via a unique N-terminal domain of this isoform. For most other Sirtuin isoforms, including mitochondrial Sirt3-5, no potent and specific activators have yet been identified. We here describe the identification and characterization of 1,4-dihydropyridine-based compounds that either act as pan Sirtuin activators or specifically stimulate Sirt3 or Sirt5. The activators bind to the Sirtuin catalytic cores independent of NAD+ and acylated peptides and stimulate turnover of peptide and protein substrates. The compounds also activate Sirt3 or Sirt5 in cellular systems regulating, e.g., apoptosis and electron transport chain. Our results provide a scaffold for potent Sirtuin activation and derivatives specific for Sirt3 and Sirt5 as an excellent basis for further drug development.
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| Publikationsform: | Artikel in einer Zeitschrift |
|---|---|
| Begutachteter Beitrag: | Ja |
| Institutionen der Universität: | Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie > Lehrstuhl Biochemie I - Proteinbiochemie der Signaltransduktion - Univ.-Prof. Dr. Clemens Steegborn Fakultäten Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie |
| Titel an der UBT entstanden: | Ja |
| Themengebiete aus DDC: | 500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie |
| Eingestellt am: | 10 Nov 2022 08:32 |
| Letzte Änderung: | 10 Nov 2022 08:32 |
| URI: | https://eref.uni-bayreuth.de/id/eprint/72730 |