Discovery of small-molecule enzyme activators by activity-based protein profiling

Bernard P. Kok, Srijana Ghimire, Woojoo Kim, Shreyosree Chatterjee, Tyler Johns, Seiya Kitamura, Jerome Eberhardt, Daisuke Ogasawara, Janice Xu, Ara Sukiasyan, Sean M. Kim, Cristina Godio, Julia M. Bittencourt, Michael Cameron, Andrea Galmozzi, Stefano Forli, Dennis W. Wolan, Benjamin F. Cravatt, Dale L. Boger, Enrique Saez

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse—small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1—a poorly characterized serine hydrolase with complex genetic links to human metabolic traits. We apply ABPP-guided medicinal chemistry to advance a lead into a selective LYPLAL1 activator suitable for use in vivo. Structural simulations coupled to mutational, biochemical and biophysical analyses indicate that this compound increases LYPLAL1’s catalytic activity likely by enhancing the efficiency of the catalytic triad charge-relay system. Treatment with this LYPLAL1 activator confers beneficial effects in a mouse model of diet-induced obesity. These findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)997-1005
Number of pages9
JournalNature Chemical Biology
Issue number9
StatePublished - Sep 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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