Cytochrome b(5) modulation of 17{alpha} hydroxylase and 17-20 lyase (CYP17) activities in steroidogenesis.
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 C(17) position to generate 17alpha-hydroxypregnenolone and 17alpha-hydroxyprogesterone, while the second enzymic activity cleaves the C(17)-C(20) bond of 17alpha-hydroxypregnenolone and 17alpha-hydroxyprogesterone to form dehydroepiandro-sterone and androstenedione respectively. The modulation of these two activities occurs through cytochrome b(5). Association of cytochrome b(5) 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 b(5) and CYP17 are also thought to play a crucial role in the association of these two haemoproteins. Although cytochrome b(5) 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 b(5) promotes the cleavage by aligning the iron-oxygen complex attack onto the C(20) rather than the C(17) atom of the steroid substrate molecule. Thus, further understanding of the mechanism of modulation by cytochrome b(5) 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.
Akhtar
M K
MK
Institute of Biological Sciences, Cledwyn Building, University of Wales, Aberystwyth, Ceredigion SY23 3DD, UK.
Kelly
S L
SL
Kaderbhai
M A
MA
D000302:Adrenal Cortex / Q000378:metabolism*; D050499:Adrenarche / Q000502:physiology*; D002384:Catalysis; D015786:Cytochromes b5 / Q000378:metabolism*; D005260:Female; D006066:Gonads / Q000378:metabolism*; D006801:Humans; D008297:Male; D011085:Polycystic Ovary Syndrome / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D055672:Static Electricity; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis*
D013256:Steroids; D015786:Cytochromes b5; D013254:Steroid 17-alpha-Hydroxylase