Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; JST-ERATO, Japan.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Bioorg Med Chem. 2018 Oct 15;26(19):5359-5367. doi: 10.1016/j.bmc.2018.07.009. Epub 2018 Jul 7.
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.
赖氨酸酰化反应是一种至关重要的化学反应，既是一种翻译后修饰，也是一种生物偶联方法。我们之前开发了一种化学催化剂 DSH，它可以激活包括酰基辅酶 A 在内的化学稳定硫酯，从而在生理条件下实现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，如活细胞中，需要更有效的催化剂来实现高效的赖氨酸酰化，但目前还没有合理的指导方针来开发用于生理条件下而不是有机溶剂中的高效赖氨酸酰化催化剂。在这里，我们对 DSH 和几种衍生物介导赖氨酸乙酰化的能力进行了动力学分析，以更好地理解在生理条件下实现高乙酰化活性所必需的结构要素。有趣的是，反应性的获得趋势与在有机溶剂中观察到的不同，这表明与用于有机溶剂的催化剂相比，为特定于生理条件下使用而设计化学催化剂需要不同的原则。基于获得的信息，我们确定了一个具有高活性和结构灵活性的新催化剂支架，可进一步修饰以改进该催化剂体系。
