Cytosine hydrolytic deamination

S. Sun et al., Radical-mediated cytosine and S-methylcytosine hydrolytic deamination reactions. Int. J. Quantum Chem. 106, 1878-1894 (2006)... 

The electrolysis products in neutral medium included one additional absorbing substance, the chromatographic properties of which, together with its reaction with the Fink reagent to give a yellow product85), pointed to its being 5,6-dihydro-cytosine 86), further confirmed by its hydrolytic deamination to a product identical with 5,6-dihydrouracil. 

Fig. 7-2 The spontaneous hydrolytic deamination of cytosine to give uracii (top), and 5-methyicytosine to give thymine.

EXAMPLE 8.13 One of the most common ways in which bases in DNA become damaged is through hydrolytic deamination. In this way cytosine, adenine, and guanine are converted to uracil, hypoxanthine, and xanthine, respectively (Fig. 8-13). 

To summarize, at our current level of understanding, the mutagenic effect of UV light is clearly dominated by the formation of the cyclobutane pyrimidine dimers and (6—4) photoadducts. Among them, the cytosine-containing lesions are the most mutagenic lesions due to their sensitivity to hydrolytic deamination. 

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. ... 

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. 

In the early attempts to identify the nitrogenous bases of desoxy-ribosenucleic acid, some confusion arose for two reasons. At first, the products obtained by hydrolysis of nucleoprotein were studied, and there was no assurance that any particular base came from the nucleic acid rather than from the protein. Then, when the nucleic acid itself became available, the hydrolytic agents at first employed were sufficiently drastic to cause some deamination of the amino-purines (with the production of some xanthine and hypoxanthine) and some demethylation of thymine to uracil. In 1874, Piccard isolated guanine (and h3T>oxanthine) from sperm nuclein. Kossel and Neumann discovered in the hydrolysate of thymus nucleic acid two new pyrimidine bases which they named thy-mine and cytosine but they assigned incorrect empirical formulas to them. In 1894, they correctly described thymine as CsHgOjNs, but cytosine was not purified and characterized till much later. " " Levene now analyzed a series of nucleic acids from a variety of sources and found " that they all contained guanine and adenine. By mild hydrolysis of thymus nucleic acid, Steudel obtained guanine and adenine as the sole purine bases and demonstrated that they occur in equi-molecular proportions. Levene and Mandel confirmed this result and showed that the two purine bases and the two pyrimidine bases (thymine and cytosine) all occur in thymus nucleic acid in equimolecular proportions. 

Several spontaneous hydrolytic reactions also cause DNA damage. For example, it has been estimated that several thousand purine bases are lost daily from the DNA in each human cell. In depurination reactions the N-glycosyl linkage between a purine base and deoxyribose is cleaved. The protonation of N-3 and N-7 of guanine promotes hydrolysis. If repair mechanisms do not replace the purine nucleotide, a point mutation will result in the next round of DNA replication. Similarly, bases can be spontaneously deaminated. For example, the deaminated product of cytosine converts to uracil via a tautomeric shift. Eventually, what should be a CG base pair is converted to an AT base pair. (Uracil is similar in structure to thymine.)... 

Reductive P. d. (Fig.). To a certain extent, this process represents a reversal of Pyrimidine biosynthesis (see). The pyrimidine ring is partially hydrogenated, and the resulting dihydro-compound is cleaved hydrolytically. Cytosine is converted to uracil by deamination, and uracil is degraded to p-alanine. Thymine is degraded to P-aminoisobutyrate. These end-products are transaminated and metabolized to common metabolic intermediates (Fig.). 

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