The impact of aromatase mechanism on other P450s.

ABSTRACT

Experimental findings from a number of laboratories have converged to show that the conversion of androgens into oestrogen, catalysed by aromatase, involves three distinct reactions which occur at a single active site. That each one of these reactions belongs to a different generic type was revealed by chemical consideration, together with our (18)O-experiments. In particular, these findings highlighted the fact that the third reaction in the sequence occurs by a novel process for which a number of plausible mechanisms have been considered. The scrutiny of these mechanisms has involved either studies on aromatase itself, or on related enzymes which catalyse the aromatase type of cleavage reaction as generalized in equation 1 [equation see text]. The acyl-carbon cleavage reaction of equation 1 is catalysed by sterol 14alpha-demethylases, accounts for several side-chain fission products formed by CYP17 (17alpha-hydroxylase-17,20-lyase), and constitutes a weak property of certain drug metabolizing P450s, when given aliphatic aldehydes as substrates. From cumulative studies on these enzymes, consensus is beginning to emerge that the acyl-carbon fission may be promoted by the FeIII-OOH intermediate, formed during the catalytic cycles of P450s. The precedent for the direct involvement of the FeIII-OOH species in the reaction of equation 1 is influencing our thinking regarding the mechanism of the conventional hydroxylation reaction. The status of knowledge surrounding the current debate on these issues will be reviewed.