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Article: Cytochrome P450-catalyzed hydroxylation of mechanistic probes that distinguish between radicals and cations. Evidence for cationic but not for radical intermediates

TitleCytochrome P450-catalyzed hydroxylation of mechanistic probes that distinguish between radicals and cations. Evidence for cationic but not for radical intermediates
Authors
Issue Date2000
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/jacsat/index.html
Citation
Journal Of The American Chemical Society, 2000, v. 122 n. 12, p. 2677-2686 How to Cite?
AbstractOxidation of the mechanistic probes trans,trans-2-methoxy-3- phenylmethylcyclopropane and methylcubane by six cytochrome P450 isozymes has been studied. The probes differentiate between radical and cationic species in that different structural rearrangements occur for the two types of intermediates. The P450 isozymes are the phenobarbital-inducible hepatic isozymes P450 2B1 (from rat) and P450 2B4 (from rabbit), the expressed truncated isozymes P450 Δ2B4 and P450 Δ2E1 (ethanol-inducible, from rabbit), and mutants of the latter two in which an active site threonine was replaced with alanine, Δ2B4 T302A, and Δ2E1 T303A. Cationic rearrangement products were found from both probes. Oxidations of trans,trans-2-methoxy-3- phenylmethylcyclopropane gave small amounts of radical-derived rearrangement products indicating that hydroxylation occurs via insertion reactions with transition state lifetimes in the 80-200 fs range. A mechanistic description of cytochrome P450-catalyzed hydroxylations that is in accord with the present and previous radical probe results is presented. This description incorporates the recent demonstrations that two electrophilic oxidants are produced in the natural course of P450 oxidation reactions and that both electrophilic oxidant forms can effect hydroxylation reactions. Following production of a peroxo-iron species, protonation gives a hydroperoxo-iron species. Protonation of the hydroperoxo-iron species gives an iron-oxo species and water. Hydroxylations by both the hydroperoxo-iron and iron-oxo species occur by insertion reactions. The hydroperoxo-iron species inserts the elements of OH+ producing protonated alcohol products that can react in solvolysis-type reactions to give cationic rearrangement products. The iron- oxo species reacts by insertion of an oxygen atom.
Persistent Identifierhttp://hdl.handle.net/10722/167670
ISSN
2015 Impact Factor: 13.038
2015 SCImago Journal Rankings: 7.123
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorNewcomb, Men_US
dc.contributor.authorShen, Ren_US
dc.contributor.authorChoi, SYen_US
dc.contributor.authorToy, PHen_US
dc.contributor.authorHollenberg, PFen_US
dc.contributor.authorVaz, ADNen_US
dc.contributor.authorCoon, MJen_US
dc.date.accessioned2012-10-08T03:09:44Z-
dc.date.available2012-10-08T03:09:44Z-
dc.date.issued2000en_US
dc.identifier.citationJournal Of The American Chemical Society, 2000, v. 122 n. 12, p. 2677-2686en_US
dc.identifier.issn0002-7863en_US
dc.identifier.urihttp://hdl.handle.net/10722/167670-
dc.description.abstractOxidation of the mechanistic probes trans,trans-2-methoxy-3- phenylmethylcyclopropane and methylcubane by six cytochrome P450 isozymes has been studied. The probes differentiate between radical and cationic species in that different structural rearrangements occur for the two types of intermediates. The P450 isozymes are the phenobarbital-inducible hepatic isozymes P450 2B1 (from rat) and P450 2B4 (from rabbit), the expressed truncated isozymes P450 Δ2B4 and P450 Δ2E1 (ethanol-inducible, from rabbit), and mutants of the latter two in which an active site threonine was replaced with alanine, Δ2B4 T302A, and Δ2E1 T303A. Cationic rearrangement products were found from both probes. Oxidations of trans,trans-2-methoxy-3- phenylmethylcyclopropane gave small amounts of radical-derived rearrangement products indicating that hydroxylation occurs via insertion reactions with transition state lifetimes in the 80-200 fs range. A mechanistic description of cytochrome P450-catalyzed hydroxylations that is in accord with the present and previous radical probe results is presented. This description incorporates the recent demonstrations that two electrophilic oxidants are produced in the natural course of P450 oxidation reactions and that both electrophilic oxidant forms can effect hydroxylation reactions. Following production of a peroxo-iron species, protonation gives a hydroperoxo-iron species. Protonation of the hydroperoxo-iron species gives an iron-oxo species and water. Hydroxylations by both the hydroperoxo-iron and iron-oxo species occur by insertion reactions. The hydroperoxo-iron species inserts the elements of OH+ producing protonated alcohol products that can react in solvolysis-type reactions to give cationic rearrangement products. The iron- oxo species reacts by insertion of an oxygen atom.en_US
dc.languageengen_US
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/jacsat/index.htmlen_US
dc.relation.ispartofJournal of the American Chemical Societyen_US
dc.titleCytochrome P450-catalyzed hydroxylation of mechanistic probes that distinguish between radicals and cations. Evidence for cationic but not for radical intermediatesen_US
dc.typeArticleen_US
dc.identifier.emailToy, PH:phtoy@hkucc.hku.hken_US
dc.identifier.authorityToy, PH=rp00791en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1021/ja994106+en_US
dc.identifier.scopuseid_2-s2.0-0034728622en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0034728622&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume122en_US
dc.identifier.issue12en_US
dc.identifier.spage2677en_US
dc.identifier.epage2686en_US
dc.identifier.isiWOS:000086204700001-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridNewcomb, M=7101865783en_US
dc.identifier.scopusauthoridShen, R=7202935798en_US
dc.identifier.scopusauthoridChoi, SY=7408121670en_US
dc.identifier.scopusauthoridToy, PH=7006579247en_US
dc.identifier.scopusauthoridHollenberg, PF=7005863178en_US
dc.identifier.scopusauthoridVaz, ADN=7103061111en_US
dc.identifier.scopusauthoridCoon, MJ=16745837600en_US

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