Tagging Sulfenic Acids

By tweaking a chemical probe, chemists have learned that a protein modification called sulfenylation influences signaling in the epidermal growth factor receptor (EGFR), a kinase enzyme implicated in multiple cancers (Nat. Chem. Biol., DOI: 10.1038/nchembio.736). Sulfenylation, or formation of sulfenic acid (–SOH) groups, can occur if a cysteine amino acid is exposed to an oxidant such as hydrogen peroxide. Tracking occurrences of the reaction and determining their implications in living cells remain challenging because established probes lack sensitivity or cell permeability. To make their latest probe, Kate S. Carroll of Scripps Florida and coworkers replaced the azide in a previous version with an alkyne. The probe turned out to be sensitive enough to detect differences in sulfenylation rates among various proteins in human cells. The team showed that sulfenylation of a specific active-site cysteine in EGFR, Cys797, enhanced its kinase activity. That cysteine is the target of several covalent drugs under development, but the drugs are designed to latch onto the cysteine in its thiol form. This development raises interesting questions about how to design irreversible inhibitors that target amino acids subject to redox modifications such as sulfenylation, Carroll says.