The Rieske oxygenase DAF‐36 functions as a cholesterol 7‐desaturase in steroidogenic pathways governing longevity

Summary Bile acids are cholesterol‐derived signaling molecules that regulate mammalian metabolism through sterol‐sensing nuclear receptor transcription factors. In C. elegans, bile acid‐like steroids called dafachronic acids (DAs) control developmental timing and longevity by activating the nuclear receptor DAF‐12. However, little is known about the biosynthesis of these molecules. Here, we show that the DAF‐36/Rieske oxygenase works at the first committed step, converting cholesterol to 7‐dehydrocholesterol. Its elucidation as a cholesterol 7‐desaturase provides crucial biochemical evidence that such oxygenases are key steroidogenic enzymes. By controlling DA production, DAF‐36 regulates DAF‐12 activities for reproductive development and longevity and may illuminate related pathways in metazoans.