Control of Nucleophile Chemoselectivity in Cyanobactin YcaO Heterocyclases PatD and TruD

YcaO proteins are ubiquitous in living organisms, where they perform crucial post-translational modifications of peptides and proteins. They are used extensively in biotechnology in companies and academic settings around the world. They also underlie some of the most important natural products in pharmaceutical development, such as thiopeptides (thiostrepton, etc.). Here, we solve one of the major outstanding mysteries behind YcaO proteins: how they exert precision selectivity of the nucleophile. The resulting findings have major implications in understanding the >30,000 YcaO proteins currently in sequencing databases and will be used widely for precision synthetic biology applications.