Deamination of cytosine

Figure 36-23. Base excision-repair of DNA. The enzyme uracil DNA glycosylase removes the uracil created by spontaneous deamination of cytosine in the DNA. An endonuclease cuts the backbone near the defect then, after an endonuclease removes a few bases, the defect is filled in by the action of a repair polymerase and the strand is rejoined by a ligase. (Courtesy of B Alberts.)...

Deamination, the hydrolytic loss of exocyclic amino groups on the DNA bases, is typically a very slow reaction. For example, deamination of cytosine residues in dnplex DNA occnrs with a half-life of about 30,000 years under physiological conditions, and the deamination of adenine residues is still more sluggish. " Alkylation at the N3-position of cytosine (Scheme 8.5) greatly increases the rate of deamination (ty2 = 406 h). Deamination of 3-methyl-2 -deoxycytidine proceeds 4000 times faster than the same reaction in the unalkylated nucleoside. Alkylation of the N3-position in cytosine residues also facilitates deglycosylation (Jy2 = 7700 h, lower pathway in Scheme 8.5), but the deamination reaction is 20 times faster and, therefore, predominates. ... 

Answer D. Deamination of cytosine would produce uracil. 

Laliberte, J., Marquez, V.E. and Momparler, R.L. (1992) Potent inhibitors for the deamination of cytosine arabinoside and 5-aza-2 -deoxycytidine by human cytidine deaminase. 

Several nucleotide bases undergo spontaneous loss of their exocyclic amino groups (deamination) (Fig. 8-33a). For example, under typical cellular conditions, deamination of cytosine (in DNA) to uracil occurs in about one of every 107 cytidine residues in 24 hours. This corresponds to about 100 spontaneous events per day, on average, in a mammalian cell. Deamination of adenine and guanine occurs at about l/100th this rate. 

Uracil DNA glycosylases, for example, found in most cells, specifically remove from DNA the uracil that results from spontaneous deamination of cytosine. Mutant cells that lack this enzyme have a high rate of G=C to A=T mutations. This glycosylase does not remove uracil residues from RNA or thymine residues from DNA. The capacity to distinguish thymine from uracil, the product of cytosine deamination—necessary for the selective repair of the latter—may be one reason why DNA evolved to contain thymine instead of uracil (p. 293). 

Removal of abnormal bases Abnormal bases, such as uracil, which can occur in DNA either by deamination of cytosine or improper incorporation of dUTP instead of dTTP during DNA synthesis, are recognized by specific glycosylases that hydrolytically cleave them from the deoxyribose-phosphate backbone of the strand. This leaves an apyrimidinic site (or apurinic, if a purine was removed), referred to as an AP-site. 

Uracil replaces thymine as the fourth nucleobase in RNA and is a common damage product in DNA and RNA from the deamination of cytosine. The physiological... 

Figure 2 Plausible chemical mechanisms for the base-mediated deamination of cytosine. Top Deamination resulting from 1,4-addition. Bottom Deamination resulting from 1,2-addition. In both cases, only the cytosine ring is shown subsequent to hydroxide addition.

Duncan BJ, Miller J. Mutagenic deamination of cytosine residues in DNA. Nature 1980 287 560-561. 

Ehrlich M, Zhang X-Y, Imander NM. Spontaneous deamination of cytosine and 5-methylcytosine residues in DNA and replacement of 5-methylcytosine residues with cytosine residues. Mutation Res. 1990 238 277-286. 

The distribution and disposition of a drug in the body result from a complex set of physiological processes and biochemical interactions. In principle, it is possible to describe these processes and interactions in mathematical terms and, if sufficient data are available, to predict the time course of drug and metabolite(s) in different species and at specific anatomic sites (15). A physiological pharmacokinetic model was developed to predict the deamination of cytosine arabinoside (ARA-C) in humans from enzyme parameters determined from homogenates of human tissue (16). ARA-C is converted to its inactive metabolite, uracil arabinoside (ARA-U) by cytidine deaminase, the activity of which varies substantially among tissues. 

Mutagenic consequences. Spontaneous deamination of cytosine bases in DNA occurs at low but measurable frequency. Cytosine is converted into uracil by loss of its amino group. After this conversion, which base pair occupies this position in each of the daughter strands resulting from one round of replication Two rounds of replication ... 

The presence in DNA of thymine rather than uracil was an enigma for many years. Both bases pair with adenine. The only difference between them is a methyl group in thymine in place of the C-5 hydrogen atom in uracil. Why is a methylated base employed in DNA and not in RNA The existence of an active repair system to correct the deamination of cytosine provides a convincing solution to this puzzle. 

Figure 27.50. Uracil Repair. Uracil bases in DNA, formed by the deamination of cytosine, are excised and replaced by cytosine.

DMA damage results when the amino group of cytosine residues spontaneously hydrolyzes in the cell, to produce a residue of uracil plus free ammonia. The amino group of 5-methyl-cytosine spontaneously hydrolyzes at a somewhat greater rate than cytosine. For any particular residue of 5-methyJ-cytosine, its half-life for deamination is about 40,000 years (Shen et a ., 1994). The half-life for deamination of cytosine is about twice as long. These rates are very low, and researchers who study its rate have to perform their reachons for hundreds of days to be able to detect any deamination. However, when deamination does occur in our DNA, it can result in a mutation. Research has shown that the "hotspots" for mutation in p53 all actually occur at residues of 5-methyl-cytosine, and not at cytosine (Schmutle et oi, 1996),... 

The spontaneous deamination of cytosine produces a residue of uradl in the DNA helix. During replication, when DNA polymerase encounters a residue of uracil in a strand of DNA, it recognises it as a residue of thymine. The newly synthesized strands of DNA are indicated by boldface ... 

Other useful pH values are pH 1.9 where fractionation depends mostly on the number of Up residues pH 3.5 where the four main ribonucleotides may be separated and higher pH values where differences between Ap and Cp can be exploited, although Rushizky et al. (1965) did not have much success at pH 4.0-4.4 with penta-to heptanucleotides. Degradation of purine nucleotides may occur at pH 1.9, although this is not observed on DEAE-paper electrophoresis and deamination of cytosine to uridine may occur at very high pH values. 

A common mutagenic event is the deamination of cytosine in DNA to form uracil. If the damaged strand is replicated, a CG base pair in DNA will be converted to a... 

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