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INK4 p16 INK4A p15 INK4B p18 INK4C p19 INK4D

INK4 p16 INK4A p15 INK4B p18 INK4C p19 INK4D. Kip p21 Cip/WAF1 p27 Kip1 p57 Kip2. event. pathway. also p53. TNF-R1-initiated apoptotic pathways. FAS-initiated apoptotic cascade. 5'-PuPuPuC(A/T)|(T/A)GPyPyPy-N(0-13) PuPuPuC(A/T)|(T/A)GPyPyPy-3'. Mutational hotspots of p53. 245.

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INK4 p16 INK4A p15 INK4B p18 INK4C p19 INK4D

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  1. INK4 p16INK4A p15INK4B p18INK4C p19INK4D

  2. Kip p21Cip/WAF1 p27Kip1 p57Kip2

  3. event pathway also p53

  4. TNF-R1-initiated apoptotic pathways

  5. FAS-initiated apoptotic cascade

  6. 5'-PuPuPuC(A/T)|(T/A)GPyPyPy-N(0-13) PuPuPuC(A/T)|(T/A)GPyPyPy-3'

  7. Mutational hotspots of p53 245 249 282 179 175

  8. Mutational hotspots in core region of p53 Arg 273 Val 157 Arg 175 Arg 248 His 179

  9. ACTIVE SITE OF CYTOCHROME P450

  10. P450 catalytic cycle “compound I” “compound 0”

  11. peroxo-iron hydroperoxo-iron iron-oxo •nucleophilic •nucleophilic •electrophilic •electrophilic •deformylation •deformylation •predominant •predominant epoxidation hydroxylation •inserts “OH+” •inserts “O”

  12. Cytochrome P450cam, cpd I looking down from distal face camphor substrate (green) FeIV=O unit

  13. Cytochrome P450cam, cpd I, view of proximal pocket showing coordinated Cys FeIV=O unit Cys 357

  14. Homolytic cleavage Cpd II Cpd I Heterolytic cleavage

  15. CYP2C5 (rabbit) looking down into distal pocket Activity: progesterone 21-hydroxylase, benzo(a) pyrene hydroxylase, estradiol 2-hydroxylase

  16. ACCESSABILITY OF ACTIVE SITES OF BACTERIAL AND MAMMALIAN P450s CYP2C5 P450cam CYP3A4

  17. Substrate specificity (where known) PAH N-oxidation of arylamines yes (updated from IARC) steroid hydrdoxylations drugs, N-nitroso, AFB1 cyclophosphamide, anti-arrhythmic, anti-depressants, PAH, testosterone ethanol, benzene, low m.w. nitrosamines, CCl4 mycotoxins, tetracyclic antibiotics, steroids

  18. CYP1A2 allele nomenclature CYP1A2 polymorphisms http://www.imm.ki.se/CYPalleles/

  19. SUBSTRATES FOR CYP 2D6

  20. Glu 216 Asp 301 Phe 120

  21. MOLECULAR DYNAMICS MODEL OF DEBRISOQUINE DOCKING AT ACTIVE SITE OF CYP 2D6

  22. Five reaction types of cytochrome P450 1. Epoxidation of double bonds. 2. C and N hydroxylation: C-H ® C-OH or N-H ® N-OH 3. Oxidative dealkylation: C-X-CH3® C-OH + CH2O; X= O, N, S C-NH2 C-SH 4. Oxidative deamination: R-CH2-NH2® R-CH=O + NH3 5. N, S oxidation: R3N ® R3N®O ; R2S®O

  23. H - O C - X - C H C - X - C H C - X - H + C H = O 3 2 2 X = O, hemiacetal X = N, gem amino hydrin X = S, thiohemiacetal X = O , N , S Oxidative dealkylation: C-hydroxylation followed by non-enzymatic hydrolysis of the gem-substituted adduct. Oxidative deamination: C-hydroxylation followed by non-enzymatic hydrolysis of the gem-substituted adduct.

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