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.
" We identified fluorophor-free, physiological substrate sites whose deacetylation can be stimulated by resveratrol. Our results suggest Sirt1 targets contributing to physiological resveratrol effects and the revealed substrate sequence dependent outcome indicates that Sirt1 inhibition should also be involved. Excitingly, these findings reveal the possibility to develop drugs modulating Sirt1-dependent deacetylation of a single substrate or a small substrate group."
http://impactaging.c...ull/100542.html
