Hydroxamic Acid‐Piperidine Conjugate is an Activated Catalyst for Lysine Acetylation under Physiological Conditions
Hydroxamic Acid‐Piperidine Conjugate is an Activated Catalyst for Lysine Acetylation under Physiological Conditions
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异羟肟酸-哌啶缀合物是生理条件下赖氨酸乙酰化的活化催化剂
DOI：
10.1002/asia.201901737
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Kanai Motomu
中科院分区：
文献类型：
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作者：
Mizumoto Shinsuke;Xi Siqi;Fujiwara Yusuke;Kawashima Shigehiro A.;Yamatsugu Kenzo;Kanai Motomu
蛋白质赖氨酸酰化是翻译后修饰的重要化学反应，也是各种应用中蛋白质修饰的一种手段。N,N-二甲基-4-氨基吡啶 (DMAP) 衍生物是蛋白质赖氨酸酰化广泛使用的催化剂；然而，DMAP 部分由于其碱性，在生理条件下大多以质子化形式存在，因此失活。提供更高酰化活性的替代催化基序将进一步拓宽化学赖氨酸酰化的可能应用。我们在此报道，在生理条件下，异羟肟酸-哌啶缀合物 Ph-HXA 是比 DMAP 更活跃的赖氨酸乙酰化催化基序。与 DMAP 相比，异羟肟酸部分在中性 pH 值的水溶液中大部分被去质子化，从而产生更高浓度的活化形式。 Ph-HXA 催化剂比 DMAP 更能耐受高浓度谷胱甘肽导致的失活。因此，Ph-HXA 可能是细胞中靶蛋白选择性和位点选择性乙酰化的合适催化基序。
Lysine acylation of proteins is an essential chemical reaction for posttranslational modification and as a means of protein modification in various applications.N,N‐Dimethyl‐4‐aminopyridine (DMAP) derivatives are widely‐used catalysts for lysine acylation of proteins; however, the DMAP moiety mostly exists in a protonated, and thus deactivated, form under physiological conditions due to its basicity. An alternative catalytic motif furnishing higher acylation activity would further broaden the possible applications of chemical lysine acylation. We herein report that the hydroxamic acid‐piperidine conjugate Ph‐HXA is a more active catalytic motif for lysine acetylation than DMAP under physiological conditions. In contrast to DMAP, the hydroxamic acid moiety is mostly deprotonated under aqueous neutral pH, resulting in a higher concentration of the activated form. The Ph‐HXA catalyst is also more tolerant of deactivation by a high concentration of glutathione than DMAP. Therefore, Ph‐HXA might be a suitable catalytic motif for target protein‐selective and site‐selective acetylation in cells.