tailieunhanh - Báo cáo khoa học: Models and mechanisms of O-O bond activation by cytochrome P450 A critical assessment of the potential role of multiple active intermediates in oxidative catalysis

Cytochrome P450 enzymes promote a number of oxidative biotransformations including the hydroxylation of unacti-vated hydrocarbons. Whereas the long-standing consensus view of the P450 mechanism implicates a high-valent iron-oxene species as the predominant oxidant in the radicalar hydrogen abstraction/oxygen rebound pathway, more recent studies on isotope partitioning, product rearrange-ments with radical clocks , 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 | Eur. J. Biochem. 271 4335-4360 2004 FEBS 2004 doi REVIEW ARTICLE Models and mechanisms of O-O bond activation by cytochrome P450 A critical assessment of the potential role of multiple active intermediates in oxidative catalysis Peter Hlavica Walther-Straub-Institut fur Pharmakologie und Toxikologie der LMU MUnchen Germany 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 iron-oxene species as the predominant oxidant in the radicalar hydrogen abstraction oxygen rebound pathway more recent studies on isotope partitioning product rearrangements with radical clocks 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 two-state reactivity 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. Keywords hydro peroxo-iron iron-oxene O2-activation P450 biomimics P450. Introduction Cytochrome P450 P450 or CYP enzymes EC a superfamily of b-type hemoproteins found in organisms from all domains of

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