Mechanistic consideration of P-450 dependent enzymic reactions: studies on oestriol biosynthesis

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Abstract
Methods for the synthesis of 19-hydroxy and 19-oxo derivatives of 16α-hydroxytestosterone [(11 b) and (12b) respectively] have been developed. These compounds were labelled with 18O, 2H, and 3H at C-19 and also with 3H at C-17. The conversion of [17α-3H]-16α,19-dihydroxytestosterone (11c) into oestriol (4c), using human placental aromatase was demonstrated in good yield and it was shown that in this process the 19-oxo compound (3c) is involved as an intermediate. The use of 16α,19-hydroxytestosterone, labelled with 3H predominantly in the HSi position, led to the conclusion that in oestriol biosynthesis the step, –CH2OH→–CHO, is accompanied by the loss of HRe and in the overall process the C-19 is ejected as HCOOH. On conducting experiments with either 18O2 or substrate containing 18O at C-19 it was shown that, in the conversion of 16α-hydroxy-19-oxotestosterone into oestriol, an atom of oxygen from O2 is incorporated into the formate. These features are similar to those already established for the corresponding biosynthesis of oestrone/oestradiol from androstenedione/testosterone. Our previous postulate that in oestrogen biosynthesis the same enzyme is involved in the hydroxylation reaction, –CH3→–CH2OH, and in the conversion, –CH2OH→–CHO, as well as in the final cleavage of the C-10–C-19 bond is further developed. Attention is drawn to the fact that, if cytochrome P-450 dependent reactions are viewed to occur via a radical mechanism, then a concept can be developed which unifies the wide variety of transformations catalysed by this group of enzymes. The diversity of reactions would then arise from the alternative mode of decomposition of radical species by one or a combination of the following processes: (a) hydrogen abstraction; (b) disproportionation; (c) fragmentation; and (d) association of radicals.

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