Abstract
Sirtuins are protein deacetylases used as therapeutic targets. Pharmacological Sirt1 activation has been questioned since the in vitro activator resveratrol failed to stimulate deacetylation of several physiological substrates. We tested the influence of substrate sequence by analyzing resveratrol effects on Sirt1-dependent deacetylation of 6802 physiological acetylation sites using peptide microarrays. Resveratrol stimulated deacetylation of a small set of sites and inhibited deacetylation of another set, whereas most substrates were hardly affected. Solution assays confirmed these substrate categories, and statistical analysis revealed their sequence features. Our results reveal substrate sequence dependence for Sirt1 modulation and suggest substrates contributing to resveratrol effects.
Highlights
Sirtuins are NAD+-dependent protein deacetylases regulating metabolism and aging processes, and they were suggested to mediate lifespan extending effects of caloric restriction [1, 2]
A large body of work indicates Sirt1-dependent resveratrol effects [10,11,12], and peptide sequences terminating with the acetyllysine do not well represent physiological substrate sites
To test whether physiological deacetylation sites can respond to resveratrol-dependent Sirt1 activation, we employed a mammalian acetylome microarray system
Summary
Sirtuins are NAD+-dependent protein deacetylases regulating metabolism and aging processes, and they were suggested to mediate lifespan extending effects of caloric restriction [1, 2]. Sirtuin activation by resveratrol and other compounds is controversially debated [6, 7], since stimulation of mammalian Sirt1 against the widely used “Fluor-de-Lys” substrate [3] depended on the presence of a non-physiological fluorophor that replaces the peptide chain immediately C-terminal to the acetyllysine [8, 9]. A large body of work indicates Sirt1-dependent resveratrol effects [10,11,12], and peptide sequences terminating with the acetyllysine do not well represent physiological substrate sites.
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