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1、CytochromeP450F.G.GuengerichS.D.BlackT.Wolff,G.StroblandH.GreimSeanEkinsF.J.GonzalezLectureIntroductiontoCytochromeP450.CytochromeP450reactionsCytochromeP450StructureP450SubstratesandInhibitorspredictionanddesignIntroductionR.T.Williams-invivo,1947.Brodie–invitro,fromlate40s
2、tillthe60s.CytochromeP450enzymes(hemoproteins)playanimportantroleintheintra-cellularmetabolism.Existinprokaryoticandeukaryotic(plantsinsectsfishandmammal,aswellasmicroorganisms)DifferentP450enzymescanbefoundinalmostanytissue:liver,kidney,lungsandevenbrain.Playsimportantrolei
3、ndrugsmetabolismandxenobiotics.P450ReactionsCytochromeP450enzymescatalyzethousandsofdifferentreaction.Oxidativereactions.SH+O2+NADPH+H+SOH+H2O+NADPH+Theproteinstructureisbelievedtodeterminesthecatalyticspecificitythroughcomplementaritytothetransitionstate.GeneralFeaturesofCy
4、tochromeP450CatalysisSubstratebinding(presumablynearthesiteofthehemeligand)1-electornreductionoftheironbyflavproteinNADPHcytochromeP450reductaseReactionofferrousironwithO2toyieldanunstableFeO2complexAdditionofthesecondelectronfromNADPHorcytochromeb5HeterolyticscissionoftheFe
5、O-O(H)bondtogenerateaformal(FeO)3+Oxidationofthesubstrate.FormalabstractionofhydrogenatomorelectronRadicalrecombinationReleaseoftheproduct.OxidativeReactionsCarbonHydroxylationHeteroatomHydroxylationHeteroatomReleaseRearangementRelatedtoHeteroatomOxidationsOxidationofπ-Syste
6、mHypervalentOxygensubstrateReductiveReactionsHumansCYP450-18families,43subfamiliesCYP1drugmetabolism(3subfamilies,3genes,1pseudogene)CYP2drugandsteroidmetabolism(13subfamilies,16genes,16pseudogenes)CYP3drugmetabolism(1subfamily,4genes,2pseudogenes)CYP4arachidonicacidorfattya
7、cidmetabolism(5subfamilies,11genes,10pseudogenes)CYP5ThromboxaneA2synthase(1subfamily,1gene)CYP7Abileacidbiosynthesis7-alphahydroxylaseofsteroidnucleus(1subfamilymember)CYP7Bbrainspecificformof7-alphahydroxylase(1subfamilymember)CYP8Aprostacyclinsynthase(1subfamilymember)CYP
8、8Bbileacidbiosynthesis(1subfamilymember)CYP11steroidbiosynthesis(2subfamili
