Mechanistic studies on aromatase and related C-C bond cleaving P-450 enzymes.

Some P-450 systems, notably aromatase and 14 alpha-demethylase catalyse not only the hydroxylate reaction but also the oxidation of an alcohol into a carbonyl compound as well as a C-C bond cleavage process. All these reactions occur at the same active site. A somewhat analogous situation is noted with 17 alpha-hydroxylase-17,20-lyase that participates in hydroxylation as well as C-C bond cleavage process. The C-C bond cleavage reactions catalysed by the above enzymes conform to the general equation: [formula: see text] It is argued that all three types of reaction catalyzed by these enzymes may be viewed as variations on a common theme. In P-450 dependent hydroxylation the initially formed FeIII-O-O. species is converted into FeIII-O-OH and the heterolysis of the oxygen-oxygen bond of the latter then gives the oxo-derivative for which a number of canonical structures are possible; for example FeV = O<==>(+.)FeIV = O<==>FeIV-O.. One of these, FeIV-O. behaves like an alkoxyl radical and participates in hydrogen abstraction from C-H bond to produce FeIV-OH and carbon radical. The latter is then quenched by the delivery of hydroxyl radical from FeIV-OH. The latter species may thus be regarded as a carrier of hydroxyl radical. We have proposed that the C-C bond cleavage reaction occurs through the participation of the FeIII-O-OH species that is trapped by the electrophilic property of the carbonyl compound giving a peroxide adduct that fragments to produce an acyl-carbon cleavage. Scientific developments leading up to this conclusion are considered. In the first author's views, "The study of mechanisms is not a scientific but a cultural activity. Mechanisms do not aim at an absolute truth but are intended to be a "running" commentary on the status of knowledge in a field. As the structural knowledge in a field advances Mechanisms evolve to take note of the new findings. Just as a constructive "running" commentary provides the stimulus for higher standards of performance, so Mechanisms call for better and firmer structural information from their practitioners".