Adenine deamination

Base-Excision Repair Every cell has a class of enzymes called DNA glycosylases that recognize particularly common DNA lesions (such as the products of cytosine and adenine deamination see Fig. 8-33a) and remove the affected base by cleaving the Af-glycosyl bond. This cleavage creates an apurinic or apyrimidinic site in the DNA, commonly referred to as an AP site or abasic... 

Other DNA glycosylases recognize and remove a variety of damaged bases, including formamidopyrimidine and 8-hydroxyguanine (both arising from purine oxidation), hypoxanthine (arising from adenine deamination), and alkylated bases such as 3-methyladenine and... 

Among bacteria, adenuse was reported in E. coli (253, 254) nthree-step process whereby adenine was converted to adenosine, which was then deaminated, and finally cleaved... 

Alkylation of Adenine and Cytosine Residues can Accelerate Deamination 341... 

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. ... 

The analogons deamination reaction is not observed in l-methyl-2 -deoxy-adenosine nncleosides. ° Rather, in the adenine series, the Dimroth rearrangement occnrs (Scheme 8.4). On the contrary, in styrene adducts of 2 -deoxyadenosine, the hydroxyl residue of the adduct undergoes intramolecular reaction with the base to initiate deamination (Scheme 8.6). ° ° Similarly, cytosine residues bearing styrene adducts at the N3-position undergo rapid deamination (nearly complete deamination is seen within 75h). °°... 

One-electron oxidation of the adenine moiety of DNA and 2 -deoxyadenos-ine (dAdo) (45) gives rise to related purine radical cations 46 that may undergo either hydration to generate 8-hydroxy-7,8-dihydroadenyl radicals (47) or deprotonation to give rise to the 6-aminyl radicals 50. The formation of 8-oxo-7,8-dihydro-2 -deoxyadenosine (8-oxodAdo) (48) and 4,6-diamino-5-formamidopyrimidine (FapyAde) (49) is likely explained in terms of oxidation and reduction of 8-hydroxy-7,8-dihydroadenyl precursor radicals 47, respectively [90]. Another modified nucleoside that was found to be generated upon type I mediated one-electron oxidation of 45 by photoexcited riboflavin and menadione is 2 -deoxyinosine (51) [29]. The latter nucleoside is likely to arise from deamination of 6-aminyl radicals (50). Overall, the yield of formation of 8-oxodAdo 48 and FapyAde 49 upon one-electron oxidation of DNA is about 10-fold-lower than that of 8-oxodGuo 44 and FapyGua 43, similar to OH radical mediated reactions [91]. 

The DNA bases that contain amino groups tend to deaminate spontaneously. In particular, cytosine significantly deaminates to uracil, but adenine and guanine can also deaminate to hypoxanthine and xanthine, respectively. If not corrected, the new bases can cause serious mutations... 

The sensitivity of adenine to hydrolysis, with a half-life for deamination of 80 years at pH 7 and 310 K (at 273 K, the half-life is 4,000 years). Ring-opening reactions are also possible. 

Treatment of cordycepin with nitrous acid, and subsequent hydrolysis of the deaminated product, yields hypoxanthine, indicating that in the adenine moiety the primary amino group is free and the glycosidic linkage involves C7 or C9. The close similarity between the ultraviolet absorption spectrum of cordycepin and those of 9-methyladenine and adenosine63 (9-/3-J>-ribofuranosyladenineMa) favors the latter possibility. The complete stereoisomeric description of cordycepin (XXVIII), formulation of which... 

The isomerism existing between the pairs of nucleotides was attributed to the different locations of the phosphoryl residues in the carbohydrate part of the parent nucleoside,49 63 since, for instance, the isomeric adenylic acids are both hydrolyzed by acids to adenine, and by alkalis or kidney phosphatase to adenosine. Neither is identical with adenosine 5-phosphate since they are not deaminated by adenylic-acid deaminase,68 60 and are both more labile to acids than is muscle adenylic acid. An alternative explanation of the isomerism was put forward by Doherty.61 He was able, by a process of transglycosidation, to convert adenylic acids a" and 6 to benzyl D-riboside phosphates which were then hydrogenated to optically inactive ribitol phosphates. He concluded from this that both isomers are 3-phosphates and that the isomerism is due to different configurations at the anomeric position. This evidence is, however, open to the same criticism detailed above in connection with the work of Levene and coworkers. Further work has amply justified the original conclusion regarding the nature of the isomerism, since it has been found that, in all four cases, a and 6 isomers give rise to the same nucleoside on enzymic hydrolysis.62 62 63 It was therefore evident that the isomeric nucleotides are 2- and 3-phosphates, since they are demonstrably different from the known 5-phosphates. The decision as to which of the pair is the 2- and which the 3-phosphate proved to be a difficult one. The problem is complicated by the fact that the a and b" nucleotides are readily interconvertible.64,64... 

Mismatch Repair. Mispairs that break the normal base-pairing rules can arise spontaneously due to DNA biosynthetic errors, events associated with genetic recombination and the deamination of methylated cytosine (Modrich, 1987). With the latter, when cytosine deaminates to uracil, an endonuclease enzyme, /V-uracil-DNA glycosylase (Lindahl, 1979), excises the uracil residue before it can pair with adenine at the next replication. However, 5-methyl cytosine deaminates to form thymine and will not be excised by a glycosylase. As a result, thymine exits on one strand paired with guanine on the sister strand, that is, a mismatch. This will result in a spontaneous point mutation if left unrepaired. For this reason, methylated cytosines form spontaneous mutation hot-spots (Miller, 1985). The cell is able to repair mismatches by being able to distinguish between the DNA strand that exists before replication and a newly synthesized strand. 

For design of a simple manufacturing process, the thermostability of the NP enzymes is a very useful feature. Although heat treatment can be used as part of a purification protocol to isolate the enzymes from contaminating materials, the high temperature of operation itself excludes undesired enzyme-catalysed side reactions. For example, in the synthesis of 9-p-D-arabinofuranosyladenine from Ara-U and adenine, using a wet cell paste of Enterobacter aerogenes, adenine and Ara-U mainly underwent deamination at lower temperatures to form hypoxanthine and uracil respectively. At elevated temperature, deamination was completely eliminated and the rate of transarabinosylation increased. 

Only a few examples of the group of chemical mutagens are shown here. Nitrous acid (HNO2 salt nitrite) and hydroxylamine (NH2OH) both deaminate bases they convert cytosine to uracil and adenine to inosine. 

Adenine is deaminated to inosine by the action of adenosine deaminase. 

Amine oxidases catalyze the oxidative deamination of both xenobiotic and biogenic amines, and thus have many critical biological functions. Two distinct classes differ in the nature of their prosthetic groups [1]. The flavin-(FAD flavin adenine dinucleotide)-dependent amine oxidases include monoamine oxidases (MAO A and B) and polyamine oxidases. Amine oxidases not containing FAD, the so-called semicarbazide-sensitive amine oxidases (SSAO), include both plasma amine oxidases and tissue amine oxidases. These contain quinonoid structures as redox cofactors that are derived from posttranslationally modified tyrosine or tryptophan side chains, topaoquinone frequently playing this role [2]. 

Deamination of aminopurines Adenine undergoes deamination to produce hypoxanthine, and guanine is deaminated to xanthine. 

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. 

Figure 6.43 Mechanism of a mutagenic transformation by deamination of adenine to hypoxanthine. Hypoxanthine (Fig. 4.29) pairs like guanine, and this results in a transition A T—>G C. Source Adapted from Ref. 12.

Because of their basicity (lower than that of aliphatic amines), aromatic primary amines can be selectively nitrosated179 in the presence of aliphatic amines at low pH. An example is provided by the deamination of 3 -amino-3 -deoxyadenosine, although the yield of the product isolated, 3 -amino-3 -deoxyinosine, was180 only about 4%. Some 50% of the starting material remained unchanged, and hydrolysis released adenine (30%). 

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. 

Free guanine and hypo xanthine (the deamination product of adenine Fig. 22-45) are salvaged in the same way by hypoxanthine-guanine phosphoribosyltransferase. A similar salvage pathway exists for pyrimidine bases in microorganisms, and possibly in mammals. 

The reduction of adenine (267) is suggested to follow420 a similar route rather than that described in Part I, and that purine is formed after the first two-electron reduction and elimination of ammonia. A similar route is possibly followed in the deamination of 7-amino-6-phenylpyrazolo[l,5-a]-pyrimidine.351 Reduction followed by elimination is probably the most general reaction path for removing substituents bound to a heterocyclic ring through O, N, or S. 

Treatment of NAD+ with nitrous acid deaminates the adenine ring. The resulting deamino NAD+ as well as synthetic analogs containing the following groups in place of the carboxyamide have been used... 

As indicated in Fig. 25-18, free adenine released from catabolism of nucleic acids can be deaminated hydrolytically to hypoxanthine, and guanine can be deaminated to xanthine.328 The molybdenum-containing xanthine oxidase (Chapter 16) oxidizes hypoxanthine to xanthine and the latter on to uric acid. Some Clostridia convert purine or hypoxanthine to xanthine by the action of a selenium-containing purine hydroxylase.3283 Another reaction of xanthine occurring in some plants is conversion to the trimethylated derivative caffeine. 328b One of the physiological effects of caffeine in animals is inhibition of pyrimidine synthesis.329 However, the effect most sought by coffee drinkers may be an increase in blood pressure caused by occupancy of adenosine receptors by caffeine.330... 

In die physiological system, niacin and related substances maintain nicotinamide adenine diiuicleotide (NAD) and nicotinamide adenine ciinucleotide phosphate (NADP). Niacin also acts as a hydrogen and electron transfer agent in carbohydrate metabolism and furnishes coenzymes for dehydrogenase systems. A niacin coenzyme participates in lipid catabolism, oxidative deamination, and photo synthesis,... 

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