The diverse chemistry of cytochrome P450 17A1 (P450c17, CYP17A1)

[Display omitted] •CYP17A1 catalyzes at least 13 different reactions with endogenous steroids.•Cytochrome b5 stimulates 17,20-lyase activity and enables andiene-β-synthase activity.•Metabolic switching occurs with deuterium labeled-progesterone substrates.•Minor products can have physiologic functions. The steroid hydroxylation and carbon–carbon bond cleavage activities of cytochrome P450 17A1 (CYP17A1) are responsible for the production of glucocorticoids and androgens, respectively. The inhibition of androgen synthesis is an important strategy to treat androgen-dependent prostate cancer. We discuss the different enzymatic activities towards the various substrates of CYP17A1, demonstrating its promiscuity. Additionally, a novel interhelical interaction is proposed between the F–G loop and the B’-helix to explain the 16α-hydroxylase activity of human CYP17A1 with progesterone as the substrate. The techniques used by biochemists to study this important enzyme are also summarized. This article is part of a Special Issue entitled 'Steroid/Sterol signaling'.