INK4

p16INK4A

p15INK4B

p18INK4C

p19INK4D

Kip

p21Cip/WAF1

p27Kip1

p57Kip2

event

pathwayalso 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'

179

245 249

282

Mutational hotspots of p53

175

Arg 248

Arg 273

Arg 175

His 179

Val 157

Mutational hotspots in core region of p53

N

NN

N

CO2H

FeIII

HO2C

protoporphyrin IX (PPIX)

ACTIVE SITE OF CYTOCHROME P450

P450 catalytic cycle

“compound I”

“compound 0”

FeIII

FeII

FeII

O2

FeIII

O2-.

FeIV

O.+

O2 -2

FeIII

FeIII

OOH

FeIII

R

R

R

RR

R

R

e-

e-

H+

2H+

H2O

R(O)

H2O2, RCO3H,PhIOperoxide shunt

R(O) O2-.

R

O2

peroxo-iron hydroperoxo-iron iron-oxo

•nucleophilic •nucleophilic •electrophilic •electrophilic•deformylation •deformylation •predominant •predominant

epoxidation hydroxylation

•inserts “OH+” •inserts “O”

Cytochrome P450cam, cpd I looking down from distal face

camphor substrate (green)

FeIV=O unit

Cytochrome P450cam, cpd I, view of proximal pocket showing coordinated Cys

Cys 357

FeIV=O unit

O2 -2

FeIII

FeIII

OOH

FeIV

O

FeIII

OOH

+

FeIV

O

+ HO

HO

Homolytic cleavage

Heterolytic cleavage

Cpd I

Cpd II

CYP2C5 (rabbit) looking down into distal pocketActivity: progesterone 21-hydroxylase, benzo(a) pyrene hydroxylase, estradiol 2-hydroxylase

P450camCYP2C5

ACCESSABILITY OF ACTIVE SITES OF BACTERIAL AND MAMMALIAN P450s

CYP3A4

PAHN-oxidation of arylamines

mycotoxins, tetracyclic antibiotics, steroids

ethanol, benzene, low m.w. nitrosamines, CCl4

cyclophosphamide, anti-arrhythmic, anti-depressants, PAH, testosterone

steroid hydrdoxylationsdrugs, N-nitroso, AFB1

Substrate specificity (where known)

yes (updated from IARC)

CYP1A2 polymorphisms

Allele Protein Nucleotide changesReference seq:  AC091230.23

Trivial name Effect Enzyme activity References

In vivo In vitro

CYP1A2*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, 1999

CYP1A2*1C

CYP1A2.1

-3860G>A     Decreased   Nakajima et al, 1999

CYP1A2*1D

CYP1A2.1

-2467delT         Japanese patent number 05719026 Chida et al, 1999

CYP1A2*1E

CYP1A2.1

-739T>G         Japanese patent number 05719026 Chida et al, 1999

CYP1A2*1F

CYP1A2.1

-163C>A     Higher inducibility

  Japanese patent number 05719026 Sachse et al, 1999 Chida et al, 1999

CYP1A2*1G

CYP1A2.1 -739T>G; 5347T>C         Chevalier et al, 2001

http://www.imm.ki.se/CYPalleles/

SUBSTRATES FOR CYP 2D6

Asp 301

Glu 216

Phe 120

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

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-SH4. Oxidative deamination: R-CH2-NH2 R-CH=O + NH3

5. N, S oxidation: R3N R3NO ; R2SO

Five reaction types of cytochrome P450O

C C

Oxidative 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-CH3 C-X -CH

2C -X-H + CH

2=O

X=O , N , S

H -O

X = O, hemiacetal

X = N, gem amino hydrin

X = S, thiohemiacetal