Nucleic Acids in Acid and Base

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Nucleic Acids in Acid and Base
The glycosidic bond of DNA and RNA is hydrolyzed
by acids. DNA is quite stable under basic
conditions. RNA is readily hydrolyzed by base.
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Acidic hydrolysis of a glycosidic bond
Order of stability of glycosidic bonds in nucleic
acids dA, dG lt rA, rG lt dC, dT lt rC, rU
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Acidic hydrolysis of a glycosidic bond
Order of stability of glycosidic bonds in nucleic
acids dA, dG lt rA, rG lt dC, dT lt rC, rU dA, dG
hydrolyzed in boiling 0.1 M hydrochloric acid in
30 min rA, rG hydrolyzed in boiling 1 M
hydrochloric acid in 60 min rC, rU hydrolyzed in
boiling 12 M perchloric acid in 60 min
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RNA is hydrolyzed under alkaline (basic)
conditions
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Methylation of Nucleotide bases
Certain nucleotide bases in DNA molecules are
methylated. Methylation is catalyzed by enzymes
in a cell. Adenine and Cytosine are methylated
more often than Guanine and Thymine. Methylation
is usually confined to specific regions of
DNA and aid in biological processes. DNA of the
bacterium E. coli is methylated to
distinguish its DNA from that of foreign
invaders. In eukaryotic cells about 5 of
cytidines are methylated. 5-methylcytidine is
produced.
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Structures of Methylated Bases
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Spontaneous Alterations in Nucleic Acids
In a human cell, nucleotide bases of DNA
undergo spontaneous alterations in
structure. These alterations are called
mutations. As a cell ages, the number of
mutations increases, making it likely that a
cells normal processes may be altered. There is
a link between spontaneous mutation, aging, and
carcinogenesis.
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Depurination
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Deamination of 5-methylcytosine to thymine
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Deamination of adenine to hypoxanthine
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Deamination of guanine to xanthine
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Deamination of cytosine to uracil
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Why does DNA contain thymine and not uracil?
Hypothesis If DNA contined uracil, during
replication of DNA the uracils would be
base-paired with adenine. Deaminated cytosines
would also be base-paired with adenine. This
would decrease the number of G-C base pairs over
time and increase the number of A-U base
pairs. Eventually all the G-C base pairs could be
lost. The genetic code would not exist as we know
it.
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DNA damage byChemical and Environmental Agents
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Ultraviolet light is damaging to DNA
Near-UV radiation (wavelengths of 200 400 nm)
is a significant portion of the solar
spectrum. Upon exposure to ultraviolet radiation,
two adjacent pyrimidine bases can dimerize. This
happens most often between two adjacent
thymines. Two products often form cyclobutane
thymine dimer 6-4 photoproduct
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Reaction of UV light with adjacent thymines in DNA
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Thymine dimers will cause a kink in the DNA
double helix
The thymines in this region,if not repaired, can
be incorrectly replicated.
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Chemical agents that cause DNA damage
Aromatic nitrogen compounds (cytochrome P-450
metabolism) Alkylating agents (Mustard gas,
dimethylsulfate) Nitroso compounds (food
preservatives) Polycyclic aromatic hydrocarbons
(PAH)
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Aromatic Nitrogen compounds
In the 1890s bladder cancer among workers in a
dye factory was investigated. Aromatic
nitrogen compounds were found to be causing the
cancers. The compounds themselves are not
carcinogenic, but are converted to carcinogens
upon metabolism. Example 2-acetylaminofluorene
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Aromatic Nitrogen compounds
acetyl transferase
sulfotransferase
DNAbinding N-2
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Aromatic Nitrogen compounds
Aromatic nitrogen compounds are found in cooked
meat due to pyrolysis of tryptophan and
glutamine. Up to 1 ppm.
(80 ng of this compoundhas been found in
asingle cigarette)
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Alkylating agents
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Alkylating agents
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Dimethylsulfate reactionwith guanine to
formO6-Methylguanine.
O6-Methylguanine cannotbase pair with cytosine
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Modification of guanine by mustard reagents to
form mono and bi-functional products at the N-7
position
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Nitroso Compounds
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Nitroso Compounds
Nitrous acid is produced intracellularly from
nitrates and nitrites. Nitrous acid is a potent
accelerator of the deamination of bases
Deamination of 5-methylcytosine to thymine
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Cytochrome P-450 metabolism of dimethylnitrosamine
results in a DNA methylating reagent
Virtually all nitrogen and oxygen residues are
methylated
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Polycyclic aromatic hydrocarbons (PAH)
Polycyclic aromatic hydrocarbons are industrial
carcinogens An example is benzo(a)pyrene, found
in soot. PAHs are metabolized to
carcinogenic epoxides
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Polycyclic aromatic hydrocarbons (PAH)
Epoxidehydrolase
Cyt P-450
DNABinding N-2