Cytidine deamination

Base excision repair (BER), in which a single damaged base is excised and replaced, also uses Pol I to replace the modified nucleotide. BER is involved predominately in the repair of apuriruc and apyrimidiruc nucleotides [abasic (AP) sites) that frequently develop from spontaneous hydrolysis (reviewed in Reference 75). Importantly, BER is also responsible for removing uracil from DNA, which is the product of cytidine deamination. Bases modified by oxidation and alkylation are also repaired however, these modifications occur less frequently. 

Different types of substitution/conversion-editing have been described. The best characterised involves cytidine deamination to uridine in the editing of transcripts for apolipoprotein B, and adenosine deamination to inosine in the editing of the transcripts encoding the glutamate receptor subunits. More than 90 different types of base modifications have been described. Moreover, methylations and substitutions of the ribose and phosphate moieties have also been identified. Recently, the 2 -0-ribose methylation has been the focus of much attention since the discovery that the snoRNA guides the methylation in a frans-acting fashion. 

Similar to adenosine deamination, cytidine deamination replaces the amino group at the C" carhon of cytidine with a carbonyl group and forms uridine (U). As with the A to I conversion, C to U conversion has been observed in both mRNA precursors and tRNAs. However, in most of the cases that have been found so far, C to U editing takes place at pre-mRNAs, as it was first identified in the mRNA precursor of apolipoprotein B... 

Figure 17 Proposed catalytic mechanism for cytidine deamination of ApoB mRNA by APOBECI and ACF. Two uridines thought to be first recognized by ACF are labeled with red stars. Reproduced from C. Maris J. Masse A. Chester ...

Ramiro, A. R., Stavropoulos, P., Jankovic, M., and Nussenzweig, M. C. (2003). Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nat. Immunol. 4, 452-456. 

The susceptibilities of some of these fluorinated purine nucleosides to the action of enzymes are now described. In contrast to the inertness of the 2 -deoxy-2 -fluoro- and 3 -deoxy-3 -fluorocytidine analogs 739, 744, and 821 towards cytidine deaminase, the adenosine compounds 867, 883, and 906 are readily deaminated - by the adenosine deaminase in erythrocytes and calf intestine, but the resulting (deaminated) inosine compounds (from 867 and 883), as well as 888, are highly resistant - to cleavage by purine nucleoside phosphorylase (to give hypoxanthine base for the first two). The reason was discussed. Both 867 and 883 can form the 5 -triphosphates, without deamination, in human erythrocytes or murine sarcoma cells in the presence of 2 -deoxycoformycin, an adenosine deaminase inhibitor, but... 

Cytidine is the most labile of the four nucleosides (see Sect. 6.2). It deaminates spontaneously to uridine (t1/ = 340 years at pH 7 and 298 K). This was possibly the reason that cytidine was not present in the original genetic material on the primeval Earth. 

If it is desired to isolate only the pyrimidine nucleosides, hydrolysis of the nucleic acid may be carried out in acid medium.6 This process, however, entails extensive deamination of cytidine to uridine. The pyrimidine... 

Morgan, H.D., Dean, W., Coker, H.A., Reik, W. and Petersen-Mahrt, S.K (2004) Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues implications for epigenetic reprogramming. The Journal of Bioh ad Chemistry, 279, 52353-52360. 

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. 

Cytidine is deaminated to uridine and deoxycytidine is deaminated to de-oxyuridine. 

The relatively acidic thiol on serum albumin forms a fairly stable S-nitroso adduct with nitric oxide, which may serve to preserve and carry NO throughout the circulatory system [162,163]. Bacterial toxins released in toxic-shock syndrome induce excessive NO-synthase activity in macrophages. The resulting arterial expansion may induce the cardiovascular collapse associated with toxic shock syndrome [164]. Nitrous acid reacts with DNA to form dG-N2-dG interstrand crosslinks at the sequence 5 CG [165]. NO can also deaminate cytidine [166] and deoxyguanosine [167] and so may function as a mutagen. The rate law for NO reacting with O2 has been measured electrochemically as [168] ... 

Becker et al.174 find that the photoproduct of cytidine-3 -phosphate is the photohydrate. The quantum yield is dependent on the pH, and is higher for the neutral form than for the acidic form. Albert176 has published a review article on nonphotolytic hydration of the C=N bond in many heteroaromatic substances, a reaction similar in many respects to photohydration of the pyrimidines. Shapiro and Klein175 report that cytidine and cytosine are deaminated at 95°C by a variety of aqueous buffers. The reaction is pH sensitive. 

F. Garofolo, H. Pang, M. McIntosh, E. Wong, M. Kennedy, and A. Marland, Quantitation of a cytidine analog and its deaminated metabolite in animal and human plasma by LC-MS/MS, Proceedings of the 49th ASMS Conference on Mass Spectrometry,... 

Such changes can occur spontaneously or from exposure to chemicals. Cytidine can be deaminated to uridine (Fig. 6.42) and adenine to hypoxanthine (Fig. 6.43) by exposure of DNA to the oxidizing agent nitrous acid. 

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. 

An important reaction is the deamination of amines by dilute nitrous acid. This reagent, by a complex mechanism, converts the amino groups of cytidine, adenosine, and guanosine to hydroxyl groups hydroxy compounds tautomerize to the corresponding amides (Eq. 5-14). 

Deaminases present in many cells are able to deaminate cytosine or its nucleosides or nucleotides to the corresponding uracil derivatives. Cytosine aminohydrolase (deaminase) appears to occur only in microorganisms (yeast and bacteria), but cytidine aminohydrolase is widely distributed in bacteria, plants, and mammalian tissues. A distinct deox-... 

After intravenous administration (Table 55-3), the drug is cleared rapidly, with most being deaminated to an inactive form. The ratio of the anabolic enzyme deoxycytidine kinase to the inactivating catalyst cytidine deaminase is important in determining the cytotoxicity of cytarabine. 

The pyrimidine nucleosides from ribonucleic acid (uridine and cytidine) present a more formidable problem, since they cannot be hydrolyzed by dilute mineral acid, and the use of concentrated acid usually destroys the sugar moiety. It was observed, however, that simultaneous bromination, hydrolysis, and oxidation of cytidine (with bromine-hydrobromic acid) yields 5-bromouracil plus D-ribonic acid.60 Since cytidine can be deaminated to uridine with nitrous acid,61 both of these pyrimidine nucleosides must... 

Pharmacokinetics Ara-C is not effective when given orally because of its deamination to the noncytotoxic uracil arabinoside (ara-U) by cytidine deaminase in the intestinal mucosa. Given IV, it distributes throughout the body, but does not penetrate the CNS in sufficient amounts to be effective against meningeal leukemia. However, it may be injected intrathecally. Ara-C undergoes exten-... 

In accordance with the foregoing, i.e. that substitution at Nt does not affect the reduction pathway, the nucleoside and nucleotide react at the mercury electrode essentially like the bases36 37 but adsorb more strongly than cytosine at a potential more positive than —1.6 V 37,48). The EI/2 for the reduction wave in the cytosine series becomes more positive in the order base > nucleotide > nucleoside, and is linearly pH-dependent 37,53). The mechanism for electrochemical reduction of cytosine, cytidine, CMP and CpC have been considered in terms of their structure, association in solution and adsorption 37). It was concluded that the deamination step for CpC occurs very slowly or not at all 37). 

Cytidine deaminase is found in liver and polymorphonuclear leukocytes. It catalyzes the deamination of cytidine and its analogs to the corresponding uridine compounds. 

Irradiation of cytosine, cytidine, and 2 -deoxycytidine has recently been reported to produce 4,5 -linked dimers (154 R = H, j3-D-ribose, 2-deoxy-/3-D-ribose, respectively) 210 this reaction is accompanied by deamination. Photodimerization (in aqueous solution) of uracil211 and thymine212 affords the 4,6 -linked dimer (155 R = R = H and Me, respectively) the oxetane (156) (probably formed by 1,2-cycloaddition of a triplet carbonyl to an olefinic bond) is proposed as the precursor.212... 

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