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

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

16. Mutational hotspots of p53
179
245
249
282
Mutational hotspots of p53
175

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

18. ACTIVE SITE OF CYTOCHROME P450

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

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

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

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

23. Homolytic cleavage
Cpd II
Cpd I
Heterolytic cleavage

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

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

27. 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

29. CYP1A2 allele nomenclature
CYP1A2 polymorphisms
Allele
Protein
Nucleotide changes Reference seq:  AC
Trivial name
Effect
Enzyme activity
References
In vivo
In vitro
CYP1A2*1A
CYP1A2.1
None
Wild-type
Normal
Ikeya et al, Quattrochi and Tukey, 1989 
CYP1A2*1B
5347T>C
Nakajima et al, Welfare et al, 1999
CYP1A2*1C
-3860G>A
Decreased
Nakajima et al, 1999
CYP1A2*1D
-2467delT
Japanese patent number Chida et al, 1999
CYP1A2*1E
-739T>G
CYP1A2*1F
-163C>A
Higher inducibility
Japanese patent number Sachse et al, Chida et al, 1999
CYP1A2*1G
-739T>G; 5347T>C
Chevalier et al, 2001

30. SUBSTRATES FOR CYP 2D6

31. Glu 216
Asp 301
Phe 120

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

33. 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

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