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首页> 外文期刊>Chemistry: A European journal >A Fluorescence-Lifetime-Based Binding Assay for Class IIa Histone Deacetylases
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A Fluorescence-Lifetime-Based Binding Assay for Class IIa Histone Deacetylases

机译：用于IIA类组蛋白脱乙酰酶的荧光 - 寿命的结合测定

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摘要

Class IIa histone deacetylases (HDACs) show extremely low enzymatic activity and no commonly accepted endogenous substrate is known today. Increasing evidence suggests that these enzymes exert their effect rather through molecular recognition of acetylated proteins and recruiting other proteins like HDAC3 to the desired target location. Accordingly, class IIa HDACs like bromodomains have been suggested to act as "Readers" of acetyl marks, whereas enzymatically active HDACs of class I or IIb are called "Erasers" to highlight their capability to remove acetyl groups from acetylated histones or other proteins. Small-molecule ligands of class IIa histone deacetylases (HDACs) have gained tremendous attention during the last decade and have been suggested as pharmaceutical targets in several indication areas such as cancer, Huntington's disease and muscular atrophy. Up to now, only enzyme activity assays with artificial chemically activated trifluoroacetylated substrates are in use for the identification and characterization of new active compounds against class IIa HDACs. Here, we describe the first binding assay for this class of HDAC enzymes that involves a simple mix-and-measure procedure and an extraordinarily robust fluorescence lifetime readout based on [1,3]dioxolo[4,5-f]benzodioxole-based ligand probes. The principle of the assay is generic and can also be transferred to class I HDAC8.
机译：类IIA类组蛋白脱乙酰酶（HDACs）显示出极低的酶活性，并且今天没有公共所接受的内源基质。越来越多的证据表明，这些酶在乙酰化蛋白的分子识别和募集HDAC3等其他蛋白质募集到所需的靶位置的效果。因此，已经提出了溴阳瘤等类IIA HDACs作为乙酰痕的“读者”，而I类或IIB的酶活性HDAC称为“橡皮擦”，以突出其能力从乙酰化的组蛋白或其他蛋白质中除去乙酰基。在过去的十年中，IIA类甲蛋白脱乙酰酶（HDACs）的小分子配体在过去十年中获得了巨大的关注，并且已在癌症，亨廷顿的疾病和肌肉萎缩等几种指示领域中提出了药物靶标。到目前为止，仅用于人造化学活化的三氟乙酰化基材的酶活性测定用于鉴定和表征针对IIA类HDACs的新活性化合物。这里，我们描述了这种HDAC酶的第一种结合测定，其涉及简单的混合和测量程序和基于[1,3]二氧杂环[4,5-F]苯二氧吲哚基配体的异常鲁棒荧光寿命读出探针。测定原理是通用的，也可以转移到I类HDAC8。

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