Molecular Switches Turn On Proenzymes

With the help of a high-throughput screen, researchers at the University of California, San Francisco, have uncovered the first nonnatural small molecules that activate proenzymes, which are inactive enzyme precursors (Science 2009, 326, 853). Such activators could help scientists understand and manipulate the biochemistry behind cell death, blood clotting, and other fundamental pathways. Most proteases are stored as proenzymes until another protease comes along to activate them or the protease activates itself. James A. Wells and coworkers found small molecules capable of bypassing that regulation. Their screen uncovered compound 1541, a substituted coumarin that turns on two cysteine protease proenzymes called procaspase-3 and procaspase-6. In its active form, caspase-3 is critical for carrying out the final steps of apoptosis. The UCSF team showed that compound 1541 and some of its analogs induce apoptosis in a variety of cell lines, including cancer cell lines, by activating the caspases. The researchers propose that these compounds work by trapping a form of the proenzyme that is more capable of activating itself.