A Nucleophilic Chemical Probe Targeting Electrophilic Functional Groups in an Untargeted Way to Explore Cysteine Modulators in Natural Products
A Nucleophilic Chemical Probe Targeting Electrophilic Functional Groups in an Untargeted Way to Explore Cysteine Modulators in Natural Products
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以非靶向方式靶向亲电官能团的亲核化学探针探索天然产物中的半胱氨酸调节剂
DOI：
10.1021/acschembio.2c00385
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Chuan Bai
中科院分区：
文献类型：
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作者：
Yinyi Gao;Kaili Li;Lijun Zhang;Chu Chen;Chuan Bai
生物学相关的半胱氨酸的重要作用已经从蛋白质中发现，这些蛋白质是新药或化学工具的有希望的靶点。因此，新的亲电小分子，可以共价调节这些半胱氨酸引起了极大的兴趣。由于其极其广泛的化学多样性，亲电天然产物（NPs）已被研究作为半胱氨酸调节剂的有前途的来源。以前的研究已经开发了化学探针，以促进亲电纳米粒子的检测和分离。为了解决与目前的方法，包括其灵敏度低，高假阳性率，并依赖于执行手动处理与过多的光谱的问题，我们报告了一种化学探针，可以首先共价捕获亲电性纳米粒子从自然资源，然后产生敏感的报告离子信号，是特定的检测到的纳米粒子。我们应用这种非靶向的方法来探索自然资源中的亲电纳米粒子，发现亲电纳米粒子的复杂性超出了我们的预期。我们使用这种化学探针，以确定一个新的亲电呋喃二萜（BG-1）从银杏叶提取物的目标酰基辅酶A硫酯酶7（ACOT 7）的Cys 207。
The vital roles of biologically relevant cysteines have been discovered from proteins that are promising targets for new drugs or chemical tools. Therefore, new electrophilic small molecules that can covalently modulate these cysteines have attracted immense interest. Because of their extremely wide chemical diversity, electrophilic natural products (NPs) have been studied as promising sources of cysteine modulators. Previous studies have developed chemical probes to facilitate the detection and isolation of electrophilic NPs. To address the problems with the current methods, including their low sensitivity, high false-positive rate, and dependence on performing manual processing with a plethora of spectra, we report a chemical probe that can first covalently capture electrophilic NPs from natural resources and then produce sensitive reporter ion signals that are specific for the detected NPs. We applied this untargeted method to explore electrophilic NPs from natural resources and found that the complexity of electrophilic NPs was beyond our expectations. We used this chemical probe to identify a new electrophilic furanosesterterpene (BG-1) from an extract of Ginkgo biloba that targets the Cys207 of acyl-CoA thioesterase 7 (ACOT7).