Chemical genetic interrogation of natural variation uncovers a molecule that is glycoactivated

Natural variation in human drug metabolism and target genes can cause pharmacogenetic or interindividual variation in drug sensitivity. We reasoned that natural pharmacogenetic variation in model organisms could be systematically exploited to facilitate the characterization of new small molecules. To test this, we subjected multiple Arabidopsis thaliana accessions to chemical genetic screens and discovered 12 accession-selective hit molecules. As a model for understanding this variation, we characterized natural resistance to hypostatin, a new inhibitor of cell expansion. Map-based cloning identified HYR1, a UDP glycosyltransferase (UGT), as causative for hypostatin resistance. Multiple lines of evidence demonstrate that HYR1 glucosylates hypostatin in vivo to form a bioactive glucoside. Additionally, we delineated a HYR1 substrate motif and used it to identify another molecule modulated by glucosylation. Our results demonstrate that natural variation can be exploited to inform the biology of new small molecules, and that UGT sequence variation affects xenobiotic sensitivity across biological kingdoms.