title: A review of mechanistic studies on aromatase (CYP19) and 17α-hydroxylase-17,20-lyase (CYP17).
abstract: 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 intermediate. The latter following the transfer of another electron furnishes a ferric-peroxyanion, Fe(III)-O-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 17α-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'.
authors.affiliation: School of Biological Sciences, University of the Punjab, New Campus, Lahore, 54590, Pakistan. m.akhtar@soton.ac.uk
authors.forename: Muhammad
authors.initials: M
authors.lastname: Akhtar
authors.forename: J Neville
authors.initials: JN
authors.lastname: Wright
authors.forename: Peter
authors.initials: P
authors.lastname: Lee-Robichaud
mesh_terms: D001141:Aromatase / Q000378:metabolism*; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000378:metabolism; D005290:Ferric Compounds / Q000737:chemistry; D005296:Ferrous Compounds / Q000737:chemistry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D005290:Ferric Compounds; D005296:Ferrous Compounds; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase