C-C bond cleavage reactions catalyzed by cytochrome P450 enzymes

Oxygen-18 Labeling Defines a Ferric Peroxide (Compound 0) Mechanism in the Oxidative Deformylation of Aldehydes by Cytochrome P450 2B4

“…In conclusion, we provide oxygen-18 labeling evidence for a Compound 0 pathway in the deformylation of the classical substrate citronellal and two other phenylpropionaldehyde model substrates by P450 2B4 . This study defines P450 reactions with aldehydes and ketones that undergo C–C bond scission, although there is still ambiguity about the mechanisms for some other P450s and reactions. ,, …”

“…The 18 O labeling approach that we have employed here is applicable to other P450-catalyzed oxidative deformylations, e.g., P450 19A1-catalyzed androstenedione aromatization (vide supra) and P450 51-catalyzed lanosterol 14α-demethylation. , Although Ortiz de Montellano and co-workers employed 18 O 2 to study an oxidative terminal side chain carbon cleavage reaction of cholesterol by bacterial P450 125A1, direct evidence of Compound 0 contribution was not presented, and this question could also be addressed by employing deuterium-labeled formic acid analysis. In principle, the approach can be applied to C–C bond scissions that yield acetic acid (e.g., P450 17A1-catalyzed 17α,20-lyase reaction and P450 1A2-catalyzed side-chain cleavage of nabumetone), , but with α-ketols, the 18 O labeling results are not unambiguous. ,, …”

“…In principle, the approach can be applied to C−C bond scissions that yield acetic acid (e.g., P450 17A1-catalyzed 17α,20-lyase reaction and P450 1A2-catalyzed side-chain cleavage of nabumetone), 26,42 but with α-ketols, the 18 O labeling results are not unambiguous. 20,43,44 In conclusion, we provide oxygen-18 labeling evidence for a Compound 0 pathway in the deformylation of the classical substrate citronellal 28 and two other phenylpropionaldehyde model substrates by P450 2B4. 31 This study defines P450 reactions with aldehydes and ketones that undergo C−C bond scission, although there is still ambiguity about the mechanisms for some other P450s and reactions.…”

“…31 This study defines P450 reactions with aldehydes and ketones that undergo C−C bond scission, although there is still ambiguity about the mechanisms for some other P450s and reactions. 5,20,44 ■ ASSOCIATED CONTENT * sı Supporting Information…”

Oxygen‐18 Labeling Reveals a Mixed Fe−O Mechanism in the Last Step of Cytochrome P450 51 Sterol 14α‐Demethylation

“…We have recently reviewed the Compound 0 vs. Compound I question within the major P450 enzymes involved in C−C bond cleavage of steroids [9,13] . With P450 11A1 (cholesterol side chain cleavage enzyme), Compound I has been prepared and shown to be catalytically competent in the reaction [14] .…”