Toward understanding ubiquitin-modifying enzymes: from pharmacological targeting to proteomics

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• 作者：Jennie R. Lill¹ ; ^{jlill@gene.com" class="auth_mail} ; Ingrid E. Wertz² ; ^{ingrid@gene.com" class="auth_mail}
• 刊名：Trends in Pharmacological Sciences
• 出版年：April, 2014
• 年：2014
• 卷：35
• 期：4
• 页码：187-207
• 全文大小：1297 K

文摘

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.