Sortin1-hypersensitive mutants link vacuolar-trafficking defects and flavonoid metabolism in Arabidopsis vegetative tissues.

Sortin1 is a chemical genetic-hit molecule that causes specific mislocalization of plant and yeast-soluble and membrane vacuolar markers. To better understand its mode of action, we designed a Sortin1-hypersensitive screen and identified several Sortin1-hypersensitive and flavonoid-defective mutants. Mechanistically, Sortin1 mimics the effect of the glutathione inhibitor buthionine sulfoximine and alters the vacuolar accumulation of flavonoids, likely blocking their transport through vacuole-localized ABC transporters.

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.