Kinetic analyses and structure-activity relationship studies of synthetic lysine acetylation catalysts
Kinetic analyses and structure-activity relationship studies of synthetic lysine acetylation catalysts
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合成赖氨酸乙酰化催化剂的动力学分析及构效关系研究
DOI：
10.1016/j.bmc.2018.07.009
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发表时间：
2018
影响因子：
3.5
通讯作者：
Kanai Motomu
中科院分区：
文献类型：
--
作者：
Yamatsugu Kenzo;Furuta Masahiro;Xi Siqi;Amamoto Yoshifumi;Liu Jiaan;Kawashima Shigehiro A.;Kanai Motomu
蛋白质的赖氨酸酰化是一种重要的化学反应，既可以作为翻译后修饰，也可以作为生物缀合的方法。我们以前开发了一种化学催化剂，DSH，它激活化学稳定的硫酯，包括酰基辅酶A，允许在生理条件下的组蛋白的位点选择性赖氨酸酰化。然而，在更复杂的生物环境中，例如在活细胞中，需要更活性的催化剂用于有效的赖氨酸酰化，但是对于开发用于在生理条件下而不是在有机溶剂中使用的有效赖氨酸酰化催化剂没有合理的指导方针。我们，在此，进行了动力学分析的能力DSH和几个衍生物介导赖氨酸乙酰化，以更好地了解在生理条件下的高乙酰化活性所必需的结构元素。有趣的是，所获得的反应性趋势与在有机溶剂中观察到的反应性趋势不同，这表明与在有机溶剂中使用的催化剂相比，设计专门用于生理条件下的化学催化剂需要不同的原理。基于所获得的信息，我们确定了一种新的催化剂支架，具有高活性和结构灵活性的进一步修改，以改善这种催化剂体系。
Lysine acylation of proteins is a crucial chemical reaction, both as a post-translational modification and as a method for bioconjugation. We previously developed a chemical catalyst, DSH, which activates a chemically stable thioester including acyl-CoA, allowing the site-selective lysine acylation of histones under physiological conditions. However, a more active catalyst is required for efficient lysine acylation in more complex biological milieu, such as in living cells, but there are no rational guidelines for developing efficient lysine acylation catalysts for use under physiological conditions as opposed to in organic solvents. We, herein, conducted a kinetic analysis of the ability of DSH and several derivatives to mediate lysine acetylation to better understand the structural elements essential for high acetylation activity under physiological conditions. Interestingly, the obtained trend in reactivity was different from that observed in organic solvents, suggesting that a different principle is necessary for designing chemical catalysts specifically for use under physiological conditions compared to catalysts for use in organic solvents. Based on the obtained information, we identified a new catalyst scaffold with high activity and structural flexibility for further modification to improve this catalyst system.