A review of mechanistic studies on aromatase (CYP19) and 17α-hydroxylase-17,20-lyase (CYP17)

In the conventional P-450 dependent hydroxylation reaction, the Fe-III resting state of the enzyme, by a single electron transfer, is reduced to Fe-II, which reacts with O-2 to produce a Fe-III-O-O-center dot intermediate. The latter following the transfer of another electron furnishes a ferric-peroxyanion, (FeO)-O-III-O-, which after protonation leads to the fission of the O-O bond resulting in the formation of Fe-V=O, the key player in the hydroxylation process. Certain members of the P-450 family, including CYP17 and CYP19, catalyze, at the same active site, not only the hydroxylation process but also an acyl-carbon bond cleavage reaction which has been interpreted to involve the nucleophilic attack of the ferric-peroxyanion, Fe-III-O-O-, on the acyl carbon to furnish a tetrahedral intermediate which fragments, leading to acyl-carbon cleavage. Evidence is presented to show that in the case of CYP17 the attack of Fe-III-O-O- on the target carbon is promoted by cytochrome b(5), which acts as a conformational regulator of CYP17. It is this regulation of CYP17 that provides a safety mechanism which ensures that during corticoid biosynthesis, which involves 17 alpha-hydroxylation by CYP17, androgen formation is avoided. Finally, a brief account is presented of the inhibitors, of the two enzymes, which have been designed on the basis of their mechanism of action. Article from the Special issue on 'Targeted Inhibitors'. (C) 2010 Elsevier Ltd. All rights reserved.