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Development of Activity-Based Chemical Probes for Human Sirtuins
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-01-31 00:00:00 , DOI: 10.1021/acschembio.7b00754 Elysian Graham 1 , Stacia Rymarchyk 1 , Marci Wood 1 , Yana Cen 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-01-31 00:00:00 , DOI: 10.1021/acschembio.7b00754 Elysian Graham 1 , Stacia Rymarchyk 1 , Marci Wood 1 , Yana Cen 1
Affiliation
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Sirtuins consume stoichiometric amounts of nicotinamide adenine dinucleotide (NAD+) to remove an acetyl group from lysine residues. These enzymes have been implicated in regulating various cellular events and have also been suggested to mediate the beneficial effects of calorie restriction (CR). However, controversies on sirtuin biology also peaked during the past few years because of conflicting results from different research groups. This is partly because these enzymes have been discovered recently and the intricate interaction loops between sirtuins and other proteins make the characterization of them extremely difficult. Current molecular biology and proteomics techniques report protein abundance rather than active sirtuin content. Innovative chemical tools that can directly probe the functional state of sirtuins are desperately needed. We have obtained a set of powerful activity-based chemical probes that are capable of assessing the active content of sirtuins in model systems. These probes consist of a chemical “warhead” that binds to the active site of active enzyme and a handle that can be used for the visualization of these enzymes by fluorescence. In complex native proteome, the probes can selectively “highlight” the active sirtuin components. Furthermore, these probes were also able to probe the dynamic change of sirtuin activity in response to cellular stimuli. These chemical probes and the labeling strategies will provide transformative technology to allow the direct linking of sirtuin activity to distinct physiological processes. They will create new opportunities to investigate how sirtuins provide health benefits in adapting cells to environmental cues and provide critical information to dissect sirtuin regulatory networks.
中文翻译：
基于活性的人类Sirtuins化学探针的开发。
Sirtuins消耗化学计量的烟酰胺腺嘌呤二核苷酸（NAD +）从赖氨酸残基上除去乙酰基。这些酶与调节各种细胞事件有关，也被认为介导热量限制（CR）的有益作用。但是，由于不同研究组的结果相互矛盾，关于瑟土因生物学的争议在过去几年也达到了顶峰。部分原因是因为这些酶是最近发现的，并且沉默调节蛋白和其他蛋白质之间复杂的相互作用环使它们的表征极为困难。当前的分子生物学和蛋白质组学技术报告蛋白质丰度而不是活性瑟土因含量。迫切需要能够直接探测沉默调节蛋白功能状态的创新化学工具。我们已经获得了一套功能强大的基于活动的化学探针，能够评估模型系统中沉默调节蛋白的活性含量。这些探针由与活性酶的活性位点结合的化学“弹头”和可用于通过荧光可视化这些酶的手柄组成。在复杂的天然蛋白质组中，探针可以选择性地“突出显示”活跃的沉默调节蛋白成分。此外，这些探针还能够探测响应于细胞刺激的瑟土因活性的动态变化。这些化学探针和标记策略将提供转化技术，以使瑟土因活性与不同的生理过程直接关联。
更新日期：2018-01-31
中文翻译：
基于活性的人类Sirtuins化学探针的开发。
Sirtuins消耗化学计量的烟酰胺腺嘌呤二核苷酸（NAD +）从赖氨酸残基上除去乙酰基。这些酶与调节各种细胞事件有关，也被认为介导热量限制（CR）的有益作用。但是，由于不同研究组的结果相互矛盾，关于瑟土因生物学的争议在过去几年也达到了顶峰。部分原因是因为这些酶是最近发现的，并且沉默调节蛋白和其他蛋白质之间复杂的相互作用环使它们的表征极为困难。当前的分子生物学和蛋白质组学技术报告蛋白质丰度而不是活性瑟土因含量。迫切需要能够直接探测沉默调节蛋白功能状态的创新化学工具。我们已经获得了一套功能强大的基于活动的化学探针，能够评估模型系统中沉默调节蛋白的活性含量。这些探针由与活性酶的活性位点结合的化学“弹头”和可用于通过荧光可视化这些酶的手柄组成。在复杂的天然蛋白质组中，探针可以选择性地“突出显示”活跃的沉默调节蛋白成分。此外，这些探针还能够探测响应于细胞刺激的瑟土因活性的动态变化。这些化学探针和标记策略将提供转化技术，以使瑟土因活性与不同的生理过程直接关联。
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