Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Chem Asian J. 2020 Mar 16;15(6):833-839. doi: 10.1002/asia.201901737. Epub 2020 Feb 19.
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.
蛋白质赖氨酸酰化是一种重要的化学反应，是翻译后修饰的一种方式，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的常用催化剂；然而，由于其碱性，DMAP 部分在生理条件下大多以质子化的形式存在，因此处于失活状态。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。本文报道了在生理条件下，与 DMAP 相比，羟肟酸-哌啶偶联物 Ph-HXA 是一种更活跃的赖氨酸乙酰化催化基序。与 DMAP 不同，羟肟酸部分在水相中性 pH 下主要去质子化，从而形成更高浓度的活化形式。Ph-HXA 催化剂对高浓度谷胱甘肽失活的耐受性也高于 DMAP。因此，Ph-HXA 可能是一种适合于细胞中靶蛋白选择性和位点选择性乙酰化的催化基序。
