a molecular mechanism for direct sirtuin activation by resveratrol直接sirtuin蛋白激活白藜芦醇的分子机制.pdfVIP
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a molecular mechanism for direct sirtuin activation by resveratrol直接sirtuin蛋白激活白藜芦醇的分子机制
A Molecular Mechanism for Direct Sirtuin Activation by
Resveratrol
1 1 1 1 2
Melanie Gertz , Giang Thi Tuyet Nguyen , Frank Fischer , Benjamin Suenkel , Christine Schlicker ,
¨ 3 2 4 4 3
Benjamin Franzel , Jana Tomaschewski , Firouzeh Aladini , Christian Becker , Dirk Wolters ,
Clemens Steegborn1*
1 Department of Biochemistry, University of Bayreuth, Bayreuth, Germany, 2 Department of Physiological Chemistry, Ruhr-University Bochum, Bochum, Germany,
3 Department of Analytical Chemistry, Ruhr-University Bochum, Bochum, Germany, 4 Institute of Biological Chemistry, University of Vienna, Vienna, Austria
Abstract
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 p
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