Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Slide 36Slide 37Slide 38Slide 39Slide 40Slide 41homologues yeast human TEL1 ATM MEC1 ATR RAD53 Chk2INK4p16INK4Ap15INK4Bp18INK4Cp19INK4DKipp21Cip/WAF1p27Kip1p57Kip2eventpathwayalso p53eventpathwayalso p53TNF-R1-initiated apoptotic pathwaysFAS-initiated apoptotic cascade179245 249282Mutational hotspots of p53175Cartoon representation of the structure of the DNA‐binding (core) domain in complex with consensus DNA (PDB ID code 1TSR, chain B). The six residues that are most frequently mutated in human cancer are shown in orange. Blue spheres indicate the mutation sites in the super stable quadruple mutant T‐p53Cp53 monomer unit bound to 1/4 of a consensus sequenceR248R249R273R175G245R282ZnSymmetrical dimer of two p53 core domains bound to a DNA half‐site (PDB ID code 2AC0, molecules C and D). The core–core domain interface is made by residues from helix H1 and the L3 loop and is stabilized by contacts with the DNA half‐site.p53 dimeric complex bound to 1/2 of a consensus sequenceH1L3NNNNCO2HFeIIIHO2Cprotoporphyrin IX (PPIX)ACTIVE SITE OF CYTOCHROME P450P450 catalytic cycle“compound I”“compound 0”FeIIIFeIIFeIIO2FeIIIO2-.FeIVO.+O2-2FeIIIFeIIIOOHFeIIIRRRRRRRe-e-H+2H+H2OR(O)H2O2, RCO3H,PhIOperoxide shuntR(O) O2-.RO2Cytochrome P450cam, cpd I looking down from distal facecamphor substrate (green)FeIV=O unithydroxylation of camphorCytochrome P450cam, cpd I, view of proximal pocket showing coordinated CysCys 357FeIV=O unitFrom crystal structure: orientation of camphor in cpd I complexO2-2FeIIIFeIIIOOHFeIVOFeIIIOOH+FeIVO+HOHOHomolytic cleavageHeterolytic cleavageCpd ICpd IICYP2C5 (rabbit) looking down into distal pocketActivity: progesterone 21-hydroxylase, benzo(a) pyrene hydroxylase, estradiol 2-hydroxylaseP450camCYP2C5ACCESSABILITY OF ACTIVE SITES OF BACTERIAL AND MAMMALIAN P450sCYP3A4PAHN-oxidation of arylaminesmycotoxins, tetracyclic antibiotics, steroidsethanol, benzene, low m.w. nitrosamines, CCl4cyclophosphamide, anti-arrhythmic, anti-depressants, PAH, testosteronesteroid hydrdoxylationsdrugs, N-nitroso, AFB1Substrate specificity (where known)yes (updated from IARC)SUBSTRATES FOR CYP 2D6Asp 301Glu 216Phe 120MOLECULAR DYNAMICS MODEL OF DEBRISOQUINE DOCKING AT ACTIVE SITE OF CYP 2D6Effect of SNPs: 1R9O ~ WT with bound flurbiprophen; 1OG5 with mutations K206E, I215V, C216Y, S220P, P221A, I223L, and I224LR108flurbiprophenheme ironWT CYP 2C9 bound to flurbiprophenR108heme ironS-warfarinMutant CYP 2C9 complexed to S-warfarinCYP1A2 allele nomenclatureAllele Protein Nucleotide changes, Gene* *Position 5347 should have a T and not a C to be considered *1A.Trivial nameEffect Enzyme activity ReferencesIn vivo In vitroCYP1A2*1A CYP1A2.1 None Wild-type Normal Normal Ikeya et al, 1989 Quattrochi and Tukey, 1989 CYP1A2*1B CYP1A2.1 5347T>C Nakajima et al, 1994 Welfare et al, 1999CYP1A2*1C CYP1A2.1 -3860G>A Decreased Nakajima et al, 1999CYP1A2*1D CYP1A2.1 -2467delT Japanese patent number 05719026 Chida et al, 1999CYP1A2*1E CYP1A2.1 -739T>G Japanese patent number 05719026 Chida et al, 1999CYP1A2*1F CYP1A2.1 -163C>A Higher inducibility Japanese patent number 05719026 Sachse et al, 1999 Chida et al, 1999Han et al., 2002http://www.imm.ki.se/CYPalleles/1. Epoxidation of double bonds. 2. C and N hydroxylation: C-H  C-OH or N-H  N-OH3. Oxidative dealkylation: C-X-CH3  C-OH + CH2O; X= O, N, S C-NH2 C-SH4. Oxidative deamination: R-CH2-NH2  R-CH=O + NH35. N, S oxidation: R3N  R3NO ; R2SOFive reaction types of cytochrome P450OC COxidative dealkylation: C-hydroxylation followed by non-enzymatic hydrolysis of the gem-substituted adduct. H2N - - C H 2 H2N - - C H NH3 - + C H 2 = O H - O Oxidative deamination: C-hydroxylation followed by non-enzymatic hydrolysis of the gem-substituted adduct.C -X -C H3 C -X -C H2C -X -H + C H2=OX= O , N , SH -OX = O, hemiacetalX = N, gem amino hydrinX = S,