The Role of Sulfhydryl Reactivity of Small Molecules for the Activation of the KEAP1/NRF2 Pathway and the Heat Shock Response.
The Role of Sulfhydryl Reactivity of Small Molecules for the Activation of the KEAP1/NRF2 Pathway and the Heat Shock Response.
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DOI：
10.6064/2012/606104
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发表时间：
2012
期刊：
影响因子：
3.2
通讯作者：
Dinkova-Kostova AT
中科院分区：
文献类型：
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作者：
Dinkova-Kostova AT
KEAP1/NRF2通路和热休克反应是两种基本的细胞保护机制，通过调节具有多种保护功能的复杂基因网络的表达，使细胞在氧化、亲电和热应激条件下适应和存活。这两条通路分别受转录因子核因子-红细胞2 p45相关因子2 （NRF2）和热休克因子1 （HSF1）的独立调控。这些转录主调控因子的活性在应激条件下和遇到小分子（诱导剂）时增加，自然发生的和合成的都有。诱导剂有一个共同的化学性质：与巯基反应的能力。这种巯基反应性化合物的蛋白质靶标具有高活性的半胱氨酸残基，作为诱导剂的传感器。最初的半胱氨酸感知信号被进一步传递，影响大型基因网络的表达，进而最终影响复杂的细胞命运决定，如生与死。本文总结了多线实验证据，证明与巯基的反应性是KEAP1/NRF2途径和热休克反应的小分子双激活剂作用机制的主要决定因素。
The KEAP1/NRF2 pathway and the heat shock response are two essential cytoprotective mechanisms that allow adaptation and survival under conditions of oxidative, electrophilic, and thermal stress by regulating the expression of elaborate networks of genes with versatile protective functions. The two pathways are independently regulated by the transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2) and heat shock factor 1 (HSF1), respectively. The activity of these transcriptional master regulators increases during conditions of stress and also upon encounter of small molecules (inducers), both naturally occurring as well as synthetically produced. Inducers have a common chemical property: the ability to react with sulfhydryl groups. The protein targets of such sulfhydryl-reactive compounds are equipped with highly reactive cysteine residues, which serve as sensors for inducers. The initial cysteine-sensed signal is further relayed to affect the expression of large networks of genes, which in turn can ultimately influence complex cell fate decisions such as life and death. The paper summarizes the multiple lines of experimental evidence demonstrating that the reactivity with sulfhydryl groups is a major determinant of the mechanism of action of small molecule dual activators of the KEAP1/NRF2 pathway and the heat shock response.