Rearrangement reactions catalyzed by cytochrome P450s

Abstract

Cytochrome P450s promote a variety of rearrangement reactions both as a consequence of the nature of the radical and other intermediates generated during catalysis, and of the neighboring structures in the substrate that can interact either with the initial radical intermediates or with further downstream products of the reactions. This article will review several kinds of previously published cytochrome P450-catalyzed rearrangement reactions, including changes in stereochemistry, radical clock reactions, allylic rearrangements, "NIH" and related shifts, ring contractions and expansions, and cyclizations that result from neighboring group interactions. Although most of these reactions can be carried out by many members of the cytochrome P450 superfamily, some have only been observed with select P450s, including some reactions that are catalyzed by specific endoperoxidases and cytochrome P450s found in plants.

Elucidation of gibberellin biosynthesis in bacteria reveals convergent evolution

“…In particular, within all three pathways, 4 is formed prior to the neighboring B-ring contraction. We suggest that the C-19 carboxylate of this molecule may provide anchimeric assistance via stabilization of a non-classical C-6 carbocation intermediate that has been invoked in these CYP (KO) catalyzed ring contraction reactions 38 . Specifically, it has been proposed that B-ring contraction may proceed via a pinacol-type rearrangement (as has been utilized in chemical synthesis of GAs) 25–27 , and the presence of the nearby C-19 carboxylate could presumably promote selective formation of the carbocation at C-6 39 , although a radical mechanism is also plausible 27 .…”

Enzyme–Substrate Complementarity Governs Access to a Cationic Reaction Manifold in the P450BM3‐Catalysed Oxidation of Cyclopropyl Fatty Acids

“…This produces two isomeric cyclopropyl alcohols and, through slower ring opening reactions, two isomeric homoallylic alcohols. [7] Although the results from radical clock probes have generally been consistent with the presence of a radical intermediate in P450 mediated oxidation, [5] there have been indications that a cationic oxidation pathway also exists. [8] Experiments performed by Groves and co-workers with the non-haem iron containing protein toluene monooxygenase have shown increasing amounts of cation product as the substrate becomes less like the ideal one: [9] this led us to question whether this situation may also be true for P450s.…”

“…These compounds utilise the strain inherent in a cyclopropyl ring to report the presence of a radical a to the ring by detection of products arising from ring opening reactions. [5] Quantification of both the non-rearranged and ring-opened oxidation products coupled with knowledge of the rate of ring opening allows an upper limit of the lifetime for a radical intermediate to be calculated.…”

Identification of amino acid determinants in CYP4B1 for optimal catalytic processing of 4-ipomeanol

“…Cytochrome P450 (CYP) proteins form a large superfamily of monooxygenases that can process a wide variety of endogenous and also exogenous substrates [1–6]. This superfamily of enzymes is systematically classified into subfamilies based on their protein homologies.…”