Letter abstract
Nature Chemical Biology 3, 716 - 721 (2007)
Published online: 23 September 2007 | doi:10.1038/nchembio.2007.32
Chemical genetic interrogation of natural variation uncovers a molecule that is glycoactivated
Yang Zhao1, Tszfung F Chow1, Rachel S Puckrin1, Simon E Alfred1, Albert K Korir2, Cynthia K Larive2 & Sean R Cutler3
Natural variation in human drug metabolism and target genes can cause pharmacogenetic or interindividual variation in drug sensitivity1, 2. 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.
- Department of Cell and Systems Biology, University of Toronto, 25 Willcocks St., Toronto, Ontario M5S 3B2, Canada.
- Department of Chemistry, University of California-Riverside, 501 Big Springs Road, Riverside, California 92521, USA.
- Center for Plant Cell Biology and the Department of Botany and Plant Sciences, University of California-Riverside, 2150 Batchelor Hall, Riverside, California 92521, USA.
Correspondence to: Sean R Cutler3 e-mail: sean.cutler@ucr.edu
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