Cytochrome b5 modulates multiple reactions in steroidogenesis by diverse mechanisms

•Cyt-b5 affects multiple reactions within steroidogenesis.•Cyt-b5 mediates its effects via diverse reaction mechanisms.•Cyt-b5 modulates the output of adrenal and gonadal steroidogenesis.•Inactivating cyt-b5 mutations result in disorders of sex development.

Cytochrome b5 (cyt-b5) is a relatively small haemoprotein which plays an important role in the regulation of mammalian steroidogenesis. This unique protein has the ability to modulate the activity of key steroidogenic enzymes via a number of diverse reaction mechanisms. Cyt-b5 can augment the 17,20-lyase activity of CYP17A1 by promoting the interaction of CYP17A1 and POR; enhance the 16-ene-synthase activity of CYP17A1 by acting as an electron donor; and enhance the activity of 3βHSD by increasing the affinity of 3βHSD for its cofactor NAD+. We review the modulation of CYP17A1 and 3βHSD activity by cyt-b5 and discuss the reaction mechanisms associated with each activity. The physiological importance of cyt-b5 in regulating mammalian steroidogenesis is presented and the impact of inactivating cyt-b5 mutations are reviewed.This article is part of a Special Issue entitled 'Steroid/Sterol signaling'.