INK4 p16 INK4A p15 INK4B p18 INK4C p19 INK4D
description
Transcript of INK4 p16 INK4A p15 INK4B p18 INK4C p19 INK4D
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