Department of Protein Chemistry, Genentech, Inc., 1 DNA Way, M/S 413A, South San Francisco, CA 94080, USA.
Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way, M/S 40, South San Francisco, CA 94080, USA.
Trends Pharmacol Sci. 2014 Apr;35(4):187-207. doi: 10.1016/j.tips.2014.01.005. Epub 2014 Apr 6.
Ubiquitination is a highly conserved post-translational modification that regulates protein trafficking, function, and turnover. Ubiquitin ligases (E3s) conjugate ubiquitin polypeptides on substrates, whereas deubiquitnases (DUBs) reverse ubiquitination. Engineering of chemical antagonists and inhibitors of ubiquitin ligases and DUBs has considerably aided the study of enzymes that participate in ubiquitin modification of substrates. In addition, proteomic tools have been developed to characterize the enzymes, substrates, and modifications regulated by DUBs and E3s. Here we review inhibitors and antagonists that have been developed against DUBs and E3s, focusing on enzymes that participate in ubiquitin editing or in the reciprocal ubiquitin regulation of substrates. We outline the cellular biology that is regulated by these DUBs and E3s and highlight how the inhibitory compounds have improved our understanding of these pathways. Finally, we discuss the challenges and future directions for pharmacologically targeting ubiquitin-modifying enzymes, as well as the development of proteomic methods to evaluate ubiquitin modification of substrates.
泛素化是一种高度保守的翻译后修饰，可调节蛋白质的运输、功能和周转。泛素连接酶（E3）将泛素多聚体连接到底物上，而去泛素化酶（DUB）则逆转泛素化。泛素连接酶和 DUB 的化学拮抗剂和抑制剂的工程设计极大地促进了参与泛素修饰底物的酶的研究。此外，还开发了蛋白质组学工具来表征受 DUB 和 E3 调控的酶、底物和修饰。在这里，我们回顾了针对 DUB 和 E3 开发的抑制剂和拮抗剂，重点介绍了参与泛素编辑或底物泛素相互调节的酶。我们概述了这些 DUB 和 E3 调控的细胞生物学，并强调了这些抑制性化合物如何提高我们对这些途径的理解。最后，我们讨论了针对泛素修饰酶进行药理学靶向的挑战和未来方向，以及评估底物泛素修饰的蛋白质组学方法的发展。
