Lakshminarasimhan Mahadevan, Rauh David, Schutkowski Mike, Steegborn Clemens
Department of Biochemistry, University of Bayreuth, Bayreuth, Germany.
Aging (Albany NY). 2013 Mar;5(3):151-4. doi: 10.18632/aging.100542.
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.
沉默调节蛋白是用作治疗靶点的蛋白质脱乙酰酶。由于体外激活剂白藜芦醇未能刺激几种生理底物的去乙酰化作用，因此药理学上对Sirt1的激活作用一直存在质疑。我们通过使用肽微阵列分析白藜芦醇对6802个生理乙酰化位点的Sirt1依赖性去乙酰化作用的影响，来测试底物序列的影响。白藜芦醇刺激了一小部分位点的去乙酰化作用，并抑制了另一部分位点的去乙酰化作用，而大多数底物几乎没有受到影响。溶液分析证实了这些底物类别，并且统计分析揭示了它们的序列特征。我们的结果揭示了Sirt1调节的底物序列依赖性，并表明底物对白藜芦醇的作用有贡献。
