Models and mechanisms of O‐O bond activation by cytochrome P450

Abstract

Cytochrome P450 enzymes promote a number of oxidative biotransformations including the hydroxylation of unactivated hydrocarbons. Whereas the long-standing consensus view of the P450 mechanism implicates a high-valent ironoxene species as the predominant oxidant in the radicalar hydrogen abstraction/oxygen rebound pathway, more recent studies on isotope partitioning, product rearrangements with Ôradical clocksÕ, and the impact of threonine mutagenesis in P450s on hydroxylation rates support the notion of the nucleophilic and/or electrophilic (hydro) peroxo-iron intermediate(s) to be operative in P450 catalysis in addition to the electrophilic oxenoid-iron entity; this may contribute to the remarkable versatility of P450s in substrate modification. Precedent to this mechanistic concept is given by studies with natural and synthetic P450 biomimics. While the concept of an alternative electrophilic oxidant necessitates C-H hydroxylation to be brought about by a cationic insertion process, recent calculations employing density functional theory favour a Ôtwo-state reactivityÕ scenario, implicating the usual ferryl-dependent oxygen rebound pathway to proceed via two spin states (doublet and quartet); state crossing is thought to be associated with either an insertion or a radicalar mechanism. Hence, challenge to future strategies should be to fold the disparate and sometimes contradictory data into a harmonized overall picture.

On the identity and reactivity patterns of the “second oxidant” of the T252A mutant of cytochrome P450cam in the oxidation of 5-methylenenylcamphor

“…However, it is also recognized now that Cpd I itself is not a ''single oxidant species'', since theory shows the participation of multiple spin states of Cpd I [4,5,9]. Furthermore, in cases where the formation of Cpd I is hampered, there exist experimental results that tentatively implicate the involvement of a second competent oxidant in oxidation reactions of P450 [10][11][12][13][14][15][16][17][18][19][20]. In the catalytic cycle of P450, Cpd I is generated from the precursor ferric-hydroperoxy species,…”

“…This catalytic function of P450s is important in a number of biological processes including steroid hormone biosynthesis and drug metabolism [1]. Although several proposals have been made concerning the identity of the oxidant [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23], it is widely accepted that the high-valent iron-oxo (Fe IV @O) p-cation radical intermediate, Compound I (Cpd I, see Scheme 1), is the most powerful electrophilic oxidant of all the intermediates in the catalytic cycle of P450. However, it is also recognized now that Cpd I itself is not a ''single oxidant species'', since theory shows the participation of multiple spin states of Cpd I [4,5,9].…”

A Hemin/G‐Quadruplex Acts as an NADH Oxidase and NADH Peroxidase Mimicking DNAzyme

“…Figure 1 C, inset, depicts the resulting calibration curve, which demonstrates that at a concentration of NADH corresponding to 1 10 À4 m the fluorescence changes of the catalytic process reach a saturation value. Since the mechanism of the hemin-catalyzed reductive activation of O 2 to H 2 O 2 was extensively studied, [13] we suggest the following sequence of reactions, where NADH is the electron source, as the possible route for the formation of H 2 O 2 (Scheme 1 B). In this context it should be noted that horseradish peroxidase, exhibiting NADH oxidase functions, [14] requires the ligation of the fifth axial histidine ligand to generate the active site.…”

About Oxygen, Cytochrome P450 and Titanium: Learning from Ron Estabrook

“…These two topics have been extensively reviewed over the years by many authors (Hlavica, 2004;Hannemann et al, 2007;Isin and Guengerich, 2007;Seliskar and Rozman, 2007) and should not be repeated here in detail. Rather, I would like to discuss another field into which I have recently entered and which seems to be not related to the P450 field at a first glance.…”