afb 1 -dguo adduct opposite dcyd
DESCRIPTION
AFB 1 -dGuo Adduct Opposite dCyd. O. O. P. O. O. O. H. O. H. O. Reactions of AFB 1 -dGuo adduct. O. O. O. O. C. H. 3. H. O. hydrolysis. H. H. O. H. O. O. O. O. depurination. O. O. C. H. 3. formamidopyrimidine (Fapy). H. O. H. H. O. O. O. N. H. N. N. - PowerPoint PPT PresentationTRANSCRIPT
AFB1-dGuo Adduct Opposite dCyd
Reactions of AFB1-dGuo adduct
depurination
hydrolysis
OOP
O
O OH
HO
O
apurinic site
O
O
O
N
NHN
H2N
O
OHH
H
OCH3
OO
N
O
H O
H
H O
H
O
O O C H3
O
O
O
H O
HH
O
O O C H3
O
O
N
H N
O
H2
N N
N
O
N
N
HN
N
dR
H2N
O
HO
HH
O
N
NH
HN
N
dR
H2N
O
HO
HH
CHOH2O
formamidopyrimidine
(Fapy)
Ring-opened formamido pyrimidine (FAPy) of AFB1 adduct at dGuo N7
HN
N
O
H2N N
N
dR
CH2
O
H
O Cl
HN
N
O
H2N N
N
dR
HN
N
O
H2N N
N
dR
CH2
O
Cl
H
N7-(2-oxoethyl)dGuo
N
dR
O
N
NHN
O
N
N
dRN N
N N
N
dR
N
N
N2,3-dGuo 1,N6-dAdo 3,N4-dCyd
ADDUCT OF 2-CHLOROOXIRANE WITH dGuo AND OTHER dNUCLEOSIDES
= “etheno”
3,N4-Etheno-dC opposite dGuo adduct
FORMATION OF 2-AAF ADDUCT
HN
N
N
N
O
H2NN
AcN
Ac
HN
N
N
N
O
H2N
H
N
Ac
HN
N
N
N
O
H2N
2-AAF-dGuo C8 adduct
2-AF-dGuo adduct at template junction
Common direct acting alkylating agents H2N N
O
CH3
NO
H2O
HNCH3
NO+ H2N OH
O
N-methyl-N-nitrosourea (MNU)
methylnitrosamine carbamic acid
HN N
NH
CH3
NOO2N
N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)
H2O
methylnitrosamine
HNCH3
NONH2
O
O2NN
H
+
nitrourea
H3C S OCH3
O
O
methylmethanesulfonate
H3CO S OCH3
O
O
dimethyl sulfate
O
H2C CH2
O
propiolactone
NP
O N CH2CH2Cl
O
CH2CH2Cl
cyclophosphamide
H2C CH2
O
OH3C
ethylene oxide
propylene oxide
Deamination via diazotization reaction
REACTIVE ALDEHYDES FROM LIPID PEROXIDATION AND TRICYCLIC ADDUCTS
OH
O
malondialdehyde (enol form)
N
N
N
O
N
N
dR
1,N2-propeno dG
O
N
OH
N
N
O
N
N
dR
NHO
N
N
O
N
N
dR
acrolein CH3
O
NH3C
OH
N
N
O
N
N
dR
crotonaldehyde
O
OH
N
OH
N
N
O
N
N
dR
HO
4-hydroxy-2-nonenal
4 isomers
O
OH
O
4-hydroxy-2,3-epoxynonanal
N
O
N
N
dR
N
NN
O
N
N
dR
N
N
O
1,N2-etheno dG 4 isomers
+
+
1,N2-propano dG, two isomers
R = CH2 CH3
N
R
OH
OH
N
N
O
N
N
N
HO
OH
N
R
HO
O
HO
H
N
N
O
N
N
O
HO
OH
HN N
N
O
N
N
N
HO
OH
H
CHOCHR
HO
+
dGuo from initial 2,3-epoxy-4-hydroxynonanal adducts
Quinone redox cycling is a source of reactive oxygen species (ROS)
2O2-/ + 2H+ H2O2 + O2
H2O2 + Mn+ HO + HO- + M(n+1)+
GENERATION OF HYDROXYL RADICAL (HO•) BY SUPEROXIDE DISMUTASE
(eq. 1) and the FENTON REACTION (eq. 2)
SOD(1)
(2)
N
N
NH2
OH
O
dR
N
N
NH2
O
dR
OH
OH
H
H
5-hydroxy dCyd 5,6-dihydroxy-5,6-dihydrodCyd
HN
N
O
O
dR
OH
OH
CH3
H
dThyd glycol
PRODUCTS OF ATTACK OF HYDROXYL RADICAL ON NUCLEOBASES
HN
N N
N
O
H2N
HN
N N
N
H2NOH
N
N N
N
O
H2N N
N
NH
O
NH2N
O
NH
O NH2
NH2
HN
N N
N
O
H2N
OH
H
HN
N N
HN
O
H2N
O
HN
N NH
HN
O
H2N
CHO
HO
HO
O2, H2O H2O
O2
reduction
- H2O
dZdIz
Fa pyG
8-oxo-dGuodGuo
phosphoglycolate
base propenal
nucleotide 5'-aldehyde
furfural
aerobic anaerobicboth
RO3PO HO O
CH3H
OPO3R'
O O
HO H
OPO3R'
O O
CH3 HO O
PRODUCTS OF 4' AND 5',5'' DEOXYRIBOSE HYDROGEN ABSTRACTION
R, R'= DNA strand
RO3PO H
OPO3R'
O O
HO H
OH
O O
O-
O
RO3PO
B
HH
O
O BH
OPO3R'
O
OHO
OHCH
OPO3R'
O O
OHCH
OH
O O
4'
5',5''
Formation of base propenal
Reaction of base propenal with dAdo to form M1G
N
NHN
NH
OO
OH2N
dR
HN
N N
HN
O
H2N
O
spiroiminodihydantoin(Sp)
1O2
dGuo
Oxidation of 8-oxodGuo by singlet oxygen (1O2)
Review of PAH adduct structures by NMR spectrometry:
Nicholas E. Geacintov, et al., Chem. Res. Toxicol., 1997, 10, 112.
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