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|a In the conventional P-450 dependent hydroxylation reaction, the FeIII resting state of the enzyme, by a single electron transfer, is reduced to FeII, which reacts with O2 to produce a FeIII-O-O intermediate. The latter following the transfer of another electron furnishes a ferric-peroxyanion, FeIII-O-O?, which after protonation leads to the fission of the O-O bond resulting in the formation of FeVO, 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, FeIII-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 FeIII-O-O? on the target carbon is promoted by cytochrome b5, 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?-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.
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