Sirt1 activation by resveratrol is substrate sequence-selective.
Sirt1 activation by resveratrol is substrate sequence-selective.
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DOI：
10.18632/aging.100542
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Steegborn C
中科院分区：
文献类型：
--
作者：
Lakshminarasimhan M;Rauh D;Schutkowski M;Steegborn C
Sirtuins 是用作治疗靶点的蛋白质脱乙酰酶。 Sirt1 的药理学激活一直受到质疑，因为体外激活剂白藜芦醇未能刺激几种生理底物的脱乙酰化。我们使用肽微阵列分析白藜芦醇对 6802 个生理乙酰化位点的 Sirt1 依赖性脱乙酰化的影响，测试了底物序列的影响。白藜芦醇刺激一小部分位点的脱乙酰化并抑制另一组位点的脱乙酰化，而大多数底物几乎不受影响。溶液测定证实了这些底物类别，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，并表明有助于白藜芦醇效应的底物。测试 6802 个乙酰化位点表明，白藜芦醇对 Sirt1 依赖性脱乙酰化的影响取决于底物序列，并表明与体内效应相关的底物。
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. Testing 6802 acetylation sites reveals that resveratrol effects on Sirt1-dependent deacetylation depend on substrate sequence and suggests substrates relevant for in vivo effects.
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