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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Single-step fluorescent probes to detect decrotonylation activity of HDACs through intramolecular reactions
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Single-step fluorescent probes to detect decrotonylation activity of HDACs through intramolecular reactions

机译：通过分子内反应检测HDACs的单步荧光探针

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摘要

Lysine crotonylation plays vital roles in gene transcription and cellular metabolism. Nevertheless, methods for dissecting the molecular mechanisms of decrotonyaltion remains limited. So far, there is no single-step fluorescent method developed for enzymatic decrotonylation activity detection. The major difficulty is that the aliphatic crotonylated lysine doesn't allow pi-conjugation to a fluorophore and decrotonylation can not modulate the electronic state directly. Herein, we have designed and synthesized two activity-based single-step fluorogenic probes KTcr-I and KTcr-II for detecting enzymatic decrotonylation activity. These two probes can be recognized by histone deacetylases and undergo intramolecular nucleophilic exchange reaction to generate fluorescence signal. Notably, peptide sequence-dependent effect was observed. KTcr-I can be recognized by Sirt2 more effectively, while KTcr-II with LGKcr peptide sequence preferentially reacted with HDAC3. Compared to other methods of studying enzymatic decrotonylation activity, our single-step fluorescent method has a number of advantages, such as facileness, high sensitivity, cheap facility and little material consumed. We envision that the probes developed in this study will provide useful tools to screen inhibitors which suppress the decrotonylation activity of HDACs. Such probes will be useful for further delineating the roles of decrotonylation enzyme and aid in biomarker identification and drug discovery. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：赖氨酸巴豆酰化在基因转录和细胞代谢中起着至关重要的作用。然而，剖析脱乙酰化分子机制的方法仍然有限。到目前为止，还没有一种单步荧光法用于酶脱羰活性检测。主要的困难在于脂肪族巴豆酰化赖氨酸不允许pi与荧光团结合，脱甲酰化不能直接调节电子状态。在此，我们设计并合成了两种基于活性的单步荧光探针KTcr-I和KTcr-II，用于检测酶脱甲酰化活性。这两种探针可以被组蛋白脱乙酰酶识别，并通过分子内亲核交换反应产生荧光信号。值得注意的是，观察到肽序列依赖性效应。Sirt2能更有效地识别KTcr-I，而具有LGKcr肽序列的KTcr-II优先与HDAC3反应。与其他研究酶脱甲酰化活性的方法相比，我们的单步荧光法具有操作简便、灵敏度高、设备廉价、材料消耗少等优点。我们设想，本研究中开发的探针将为筛选抑制HDAC脱甲酰化活性的抑制剂提供有用的工具。这种探针将有助于进一步阐明脱甲酰化酶的作用，并有助于生物标志物识别和药物发现。（C） 2020年爱思唯尔马森SAS。版权所有。

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