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Institute of Biological Sciences, Cledwyn Building, University of Wales, Aberystwyth, Ceredigion SY23 3DD, UK

(Requests for offprints should be addressed to M A Kaderbhai; Email: mak{at}aber.ac.uk)

CYP17 is a steroidogenic enzyme located in the zona fasciculata and zona reticularis of the adrenal cortex and gonad tissues and which has dual functions – hydroxylation and as a lyase. The first activity gives hydroxylation of pregnenolone and progesterone at the C₁₇ position to generate 17-hydroxypregnenolone and 17-hydroxyprogesterone, while the second enzymic activity cleaves the C₁₇–C₂₀ bond of 17-hydroxypregnenolone and 17-hydroxyprogesterone to form dehydroepiandro-sterone and androstenedione respectively. The modulation of these two activities occurs through cytochrome b₅. Association of cytochrome b₅ and CYP17 is thought to be based primarily on electrostatic interactions in which the negatively charged residues pair up with positively charged residues on the proximal surface of the CYP17 molecule. Non-specific interactions of the hydrophobic membrane regions of cytochrome b₅ and CYP17 are also thought to play a crucial role in the association of these two haemoproteins. Although cytochrome b₅ is known to stimulate CYP activity by contributing the second electron in the catalytic cycle, in the case of CYP17, the mechanism of cleavage stimulation proceeds via an allosteric mode. It is hypothesised that cytochrome b₅ promotes the cleavage by aligning the iron–oxygen complex attack onto the C₂₀ rather than the C₁₇ atom of the steroid substrate molecule. Thus, further understanding of the mechanism of modulation by cytochrome b₅ of the hydroxylase and lyase activities should shed new insights on developing therapeutic targets in CYP17-linked biochemical processes such as adrenarche, polycystic ovary syndrome and prostate cancer.

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