Selenocysteine as a Latent Bioorthogonal Electrophilic Probe for Deubiquitylating Enzymes.

Selenocysteine as a Latent Bioorthogonal Electrophilic Probe for Deubiquitylating Enzymes.
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DOI:
10.1021/jacs.6b05688
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发表时间:
2016-10-26
影响因子:
15
通讯作者:
Chatterjee C
Chatterjee C
中科院分区:
化学1区
文献类型:
--
作者:
Whedon SD;Markandeya N;Rana ASJB;Senger NA;Weller CE;Tureček F;Strieter ER;Chatterjee C

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去泛素化酶(DUBs)从各种细胞蛋白质中去除泛素(Ub),使真核生物泛素化成为一个动态过程。蛋白质泛素化的失调与许多人类疾病有关,迫切需要鉴定与治疗相关的Ub靶点相关的特异性DUB。我们报告了两个简易的硒代半胱氨酸为基础的战略,以产生DUB探针脱氢丙氨酸(Dha)的发展。优化的氧化或烷基化消除硒产生Dha在C-末端的Ub。通过产生衍生自Ub连接酶三联基序蛋白25(TRIM-25)的探针,证明了与Ub靶中的多个硫醇相容的烷基化消除的高效用。成功捕获TRIM-25相关的DUB,泛素特异性蛋白酶15,证明了我们用于鉴定靶特异性DUB的化学策略的多功能性。
Deubiquitylating enzymes (DUBs) remove ubiquitin (Ub) from various cellular proteins and render eukaryotic ubiquitylation a dynamic process. The misregulation of protein ubiquitylation is associated with many human diseases, and there is an urgent need to identify specific DUBs associated with therapeutically relevant targets of Ub. We report the development of two facile selenocysteine-based strategies to generate the DUB probe dehydroalanine (Dha). Optimized oxidative or alkylative elimination of Se yielded Dha at the C-terminus of Ub. The high utility of alkylative elimination, which is compatible with multiple thiols in Ub targets, was demonstrated by generating a probe derived from the Ub ligase tripartite motif protein 25 (TRIM-25). Successful capture of the TRIM-25-associated DUB, ubiquitin-specific protease 15, demonstrated the versatility of our chemical strategy for identifying target-specific DUBs.
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