Abstract 1062 Photoactivatable O-GlcNAc transferase library enables covalent chemical capture of solvent-exposed TPR domain interactions

Activity variability of enzymes that metabolize drugs can cause person to person differences in the efficacy and safety of small molecule therapeutics.This has been studied in context several key enzymes involved in drug metabolism, however, the factors that influence human carboxylesterase (CES) activity have been relatively understudied despite their established role in the hydrolysis of many xenobiotic esters.We believe that this lack of knowledge is due to the scarcity and limitations of currently available techniques to investigate CES activity.To address the need for new approaches to study CESs, we have developed new fluorogenic chemical tools that can specifically report on CES activity in living cell models of CES metabolism.Subsequently, we demonstrate our tools can identify potential CES-mediated drug interactions and use these tools to create a living cell fluorescence microscopy-based assay that can identify CES sequence-dependent activity variations.Overall, the chemical tools and approaches we generated offer valuable insights into the factors that contribute to variability in drug metabolism and will help enable personalized medicine strategies to improve patient outcomes.