The selective estrogen receptor modulator clomiphene inhibits sterol biosynthesis in Arabidopsis thaliana

Sterols are produced via complex, multistep biosynthetic pathways involving similar enzymatic conversions in plants, animals, and fungi, yielding a variety of sterol metabolites with slightly different chemical properties to exert diverse and specific functions. A tremendously diverse landscape of sterols, and sterol-derived compounds can be found across the plant kingdom, determining a wide spectrum of functions. Resolving the underlying biosynthetic pathways is thus instrumental to understanding the function and use of these molecules. In only a few plants, sterol biosynthesis has been studied using mutants. In non-model species, a pharmacological approach is required. However, this relies on only a few inhibitors. Here, we investigated a collection of inhibitors of mammalian cholesterol biosynthesis to identify new inhibitors of plant sterol biosynthesis. We showed that imidazole-type fungicides, bifonazole, clotrimazole, and econazole, inhibited the obtusifoliol 14α-demethylase CYP51 in plants. Moreover, we found that the selective estrogen receptor modulator, clomiphene, inhibited sterol biosynthesis in part by inhibiting the plant-specific cyclopropyl-cycloisomerase CPI1. These results demonstrate that rescreening of inhibitors of animal sterol biosynthesis is an easy approach for identifying novel inhibitors of plant sterol biosynthesis. The molecules used in this study expand the range of inhibitors for studying and manipulating sterol biosynthesis in the plant kingdom.