Journal
NATURE CHEMICAL BIOLOGY
Volume 12, Issue 5, Pages 367-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2051
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Funding
- US National Institutes of Health [DA033760, DK909810]
- Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]
- National Cancer Institute Cancer Center (MASS core) [P30, CA014195]
- Dr. Frederick Paulsen Chair/Ferring Pharmaceuticals
- Hewitt Foundation for Medical Research Fellowship
- Chapman Charitable Trust Fellowship
- UCSD Medical Scientist Training Program funding [T32 GM007198]
- Irving S. Sigal postdoctoral fellowship from American Chemical Society
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Enzyme classes may contain outlier members that share mechanistic, but not sequence or structural, relatedness with more common representatives. The functional annotation of such exceptional proteins can be challenging. Here, we use activity-based profiling to discover that the poorly characterized multipass transmembrane proteins AIG1 and ADTRP are atypical hydrolytic enzymes that depend on conserved threonine and histidine residues for catalysis. Both AIG1 and ADTRP hydrolyze bioactive fatty acid esters of hydroxy fatty acids (FAHFAs) but not other major classes of lipids. We identify multiple cell-active, covalent inhibitors of AIG1 and show that these agents block FAHFA hydrolysis in mammalian cells. These results indicate that AIG1 and ADTRP are founding members of an evolutionarily conserved class of transmembrane threonine hydrolases involved in bioactive lipid metabolism. More generally, our findings demonstrate how chemical proteomics can excavate potential cases of convergent or parallel protein evolution that defy conventional sequence-and structure-based predictions.
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