How evolution shaped the structure of steroidogenic cytochrome P450 11A

The cytochrome P450 enzyme 11A1 (CYP11A1) is the most important player in steroid hormone biosynthesis, catalysing the first and rate-limiting step, the side-chain cleavage of cholesterol to pregnenolone, which provides the precursor for all major steroid hormones. A resurrected ancestral isoform of CYP11A (CYP11A_N1) exhibits different substrate specificities to extant vertebrate CYP11A1 forms which implies an evolutionary change in structural features. Hence, we solved the structure of the resurrected ancestral CYP11A_N1 isoform and identified the major structural changes between ancestral and extant CYP11A isoforms that lead to different catalytic properties for cholesterol metabolism. Our work presents the first structure of an ancestral mitochondrial cytochrome P450 and highlights how structural changes shaped the evolution of steroid hormone biosynthesis.