Propargyl Amides as Irreversible Inhibitors of Cysteine Proteases—A Lesson on the Biological Reactivity of Alkynes

摘要

Oligomers of the small protein ubiquitin and of ubiquitinlike proteins such as SUMO attached to cellular proteins are the main signal in the regulation of protein turnover and lifetime in cells. Therefore, the opposing mechanisms of ubiquitinylation and of de-ubiquitinylation are carefully regulated within cells. While ligating enzymes build up ubiquitin oligomers on lysine residues of intracellular proteins, the de-ubiquitinating enzymes (DUBs) hydrolyze these protein tags (Scheme 1). The latter enzymes represent cysteine-dependent isopeptidases and can be divided into different subclasses according to their protein modifier substrate. By their action on modified cell proteins they are thought to influence diverse key cellular processes such as gene expression, DNA replication, DNA repair, cell cycle control, protein sorting, and protein halflife times. The understanding of how DUBs function in health and disease is growing rapidly.