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.

蛋白质的赖氨酸酰化是至关重要的化学反应，无论是翻译后修饰还是生物缀合方法。我们之前开发了一种化学催化剂DSH，该催化剂可激活包括酰基CoA在内的化学稳定的硫酯，可在生理条件下对组蛋白进行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来进行有效的赖氨酸酰化，但是与在有机溶剂中相反，没有合理的指导方针来开发在生理条件下使用的有效的赖氨酸酰化催化剂。我们在这里，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，以更好地了解生理条件下高乙酰化活性必不可少的结构元素。有趣的是，所获得的反应性趋势不同于在有机溶剂中观察到的趋势，这表明与用于有机溶剂的催化剂相比，设计专门用于生理条件的化学催化剂需要不同的原理。基于获得的信息，我们确定了具有高活性和结构柔性的新型催化剂支架，以进一步改性以改善该催化剂体系。这表明与用于有机溶剂的催化剂相比，设计专门用于生理条件的化学催化剂需要不同的原理。基于获得的信息，我们确定了具有高活性和结构柔性的新型催化剂支架，以进一步改性以改善该催化剂体系。这表明与用于有机溶剂的催化剂相比，设计专门用于生理条件的化学催化剂需要不同的原理。基于获得的信息，我们确定了具有高活性和结构柔性的新型催化剂支架，以进一步改性以改善该催化剂体系。