期刊
ACS CHEMICAL BIOLOGY
卷 15, 期 3, 页码 718-727出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.9b00961
关键词
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资金
- National Health and Medical Research Council of Australia (NHMRC) [GNT1091636]
- Russell and Mab Grimwade Miegunyah Fund at the University of Melbourne
- Australian Research Council (ARC) [DE180100418]
- Monash University
- National Institutes of Health [NS102722, DE026806, DK118971]
- United States Department of Defense [W81XWH1810431]
- Australian Research Council [DE180100418] Funding Source: Australian Research Council
Cathepsin X/Z/P is cysteine cathepsin with unique carboxypeptidase activity. Its expression is associated with cancer and neurodegenerative diseases, although its roles during normal physiology are still poorly understood. Advances in our understanding of its function have been hindered by a lack of available tools that can specifically measure the proteolytic activity of cathepsin X. We present a series of activity-based probes that incorporate a sulfoxonium ylide warhead, which exhibit improved specificity for cathepsin X compared to previously reported probes. We apply these probes to detect cathepsin X activity in cell and tissue lysates, in live cells and in vivo, and to localize active cathepsin X in mouse tissues by microscopy. Finally, we utilize an improved method to generate chloromethylketones, necessary intermediates for synthesis of acyloxymethylketones probes, by way of sulfoxonium ylide intermediates. In conclusion, the probes presented in this study will be valuable for investigating cathepsin X pathophysiology.
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