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A Molecular Mechanism for Direct Sirtuin Activation by Resveratrol

Sirtuins are protein deacetylases regulating metabolism, stress responses, and aging processes, and they were suggested to mediate the lifespan extending effect of a low calorie diet. Sirtuin activation by the polyphenol resveratrol can mimic such lifespan extending effects and alleviate metabolic d...

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Autores principales: Gertz, Melanie, Nguyen, Giang Thi Tuyet, Fischer, Frank, Suenkel, Benjamin, Schlicker, Christine, Fränzel, Benjamin, Tomaschewski, Jana, Aladini, Firouzeh, Becker, Christian, Wolters, Dirk, Steegborn, Clemens
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504108/
https://www.ncbi.nlm.nih.gov/pubmed/23185430
http://dx.doi.org/10.1371/journal.pone.0049761
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author Gertz, Melanie
Nguyen, Giang Thi Tuyet
Fischer, Frank
Suenkel, Benjamin
Schlicker, Christine
Fränzel, Benjamin
Tomaschewski, Jana
Aladini, Firouzeh
Becker, Christian
Wolters, Dirk
Steegborn, Clemens
author_facet Gertz, Melanie
Nguyen, Giang Thi Tuyet
Fischer, Frank
Suenkel, Benjamin
Schlicker, Christine
Fränzel, Benjamin
Tomaschewski, Jana
Aladini, Firouzeh
Becker, Christian
Wolters, Dirk
Steegborn, Clemens
author_sort Gertz, Melanie
collection PubMed
description Sirtuins are protein deacetylases regulating metabolism, stress responses, and aging processes, and they were suggested to mediate the lifespan extending effect of a low calorie diet. Sirtuin activation by the polyphenol resveratrol can mimic such lifespan extending effects and alleviate metabolic diseases. The mechanism of Sirtuin stimulation is unknown, hindering the development of improved activators. Here we show that resveratrol inhibits human Sirt3 and stimulates Sirt5, in addition to Sirt1, against fluorophore-labeled peptide substrates but also against peptides and proteins lacking the non-physiological fluorophore modification. We further present crystal structures of Sirt3 and Sirt5 in complex with fluorogenic substrate peptide and modulator. The compound acts as a top cover, closing the Sirtuin’s polypeptide binding pocket and influencing details of peptide binding by directly interacting with this substrate. Our results provide a mechanism for the direct activation of Sirtuins by small molecules and suggest that activators have to be tailored to a specific Sirtuin/substrate pair.
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spelling pubmed-35041082012-11-26 A Molecular Mechanism for Direct Sirtuin Activation by Resveratrol Gertz, Melanie Nguyen, Giang Thi Tuyet Fischer, Frank Suenkel, Benjamin Schlicker, Christine Fränzel, Benjamin Tomaschewski, Jana Aladini, Firouzeh Becker, Christian Wolters, Dirk Steegborn, Clemens PLoS One Research Article Sirtuins are protein deacetylases regulating metabolism, stress responses, and aging processes, and they were suggested to mediate the lifespan extending effect of a low calorie diet. Sirtuin activation by the polyphenol resveratrol can mimic such lifespan extending effects and alleviate metabolic diseases. The mechanism of Sirtuin stimulation is unknown, hindering the development of improved activators. Here we show that resveratrol inhibits human Sirt3 and stimulates Sirt5, in addition to Sirt1, against fluorophore-labeled peptide substrates but also against peptides and proteins lacking the non-physiological fluorophore modification. We further present crystal structures of Sirt3 and Sirt5 in complex with fluorogenic substrate peptide and modulator. The compound acts as a top cover, closing the Sirtuin’s polypeptide binding pocket and influencing details of peptide binding by directly interacting with this substrate. Our results provide a mechanism for the direct activation of Sirtuins by small molecules and suggest that activators have to be tailored to a specific Sirtuin/substrate pair. Public Library of Science 2012-11-21 /pmc/articles/PMC3504108/ /pubmed/23185430 http://dx.doi.org/10.1371/journal.pone.0049761 Text en © 2012 Gertz et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Gertz, Melanie
Nguyen, Giang Thi Tuyet
Fischer, Frank
Suenkel, Benjamin
Schlicker, Christine
Fränzel, Benjamin
Tomaschewski, Jana
Aladini, Firouzeh
Becker, Christian
Wolters, Dirk
Steegborn, Clemens
A Molecular Mechanism for Direct Sirtuin Activation by Resveratrol
title A Molecular Mechanism for Direct Sirtuin Activation by Resveratrol
title_full A Molecular Mechanism for Direct Sirtuin Activation by Resveratrol
title_fullStr A Molecular Mechanism for Direct Sirtuin Activation by Resveratrol
title_full_unstemmed A Molecular Mechanism for Direct Sirtuin Activation by Resveratrol
title_short A Molecular Mechanism for Direct Sirtuin Activation by Resveratrol
title_sort molecular mechanism for direct sirtuin activation by resveratrol
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504108/
https://www.ncbi.nlm.nih.gov/pubmed/23185430
http://dx.doi.org/10.1371/journal.pone.0049761
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