Guanine deamination

The formation of the anhydride (N2O3) from equation (3) can lead to both direct and indirect DNA damage. Direct action results from nitrosation of primary amines on DNA bases which leads to deamination and at physiological pH, N2O3 has been demonstrated to be the most important species [130]. Indirect actions are due to mutations that can arise from the deamination of bases where guanine deaminates to xanthine, mispairing of which can cause a G C to A T transition which will ultimately lead to single strand breaks [131]. 

Cytosine catalysis of nitrosative guanine deamination and interstrand cross-link formation. J. Am. Chem. Soc., 127, 7346-7358. 

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... 

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. 

Purine (left). The purine nucleotide guano-sine monophosphate (CMP, 1) is degraded in two steps—first to the guanosine and then to guanine (Gua). Guanine is converted by deamination into another purine base, xanthine. 

Dichloro-9-[2-benzoyloxyethoxymethyl]purine was prepared as a key intermediate, which upon selective substitution of the 6-chloro group by ammonia followed by deamination and then displacement of the 2-chloro group gave 9-(2-hydroxyethoxymethyl)guanine. The use of the same synthetic procedure led to a variety of analogs. Of these ACV was found to... 

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

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.

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. 

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... 

The purine bases, adenine and guanine, participate in nature by providing structural elements of nucleic acids and numerous cofactors. The deaminated products of adenine and guanine do not participate in these coenzymic functions except in a relatively few instances. For example, the relative ineffectiveness of inosine monophosphate (IMP) vs. 

The existence of two separate enzymes in animal tissues responsible for the liberation of ammonia from each of the two aminopurines, adenine and guanine, the latter specific for the free purine and the former for the nucleosides, was initially presented by Jones and his colleagues 11, 12). In 1928, Schmidt 13-15) demonstrated that AMP aminohy-drolase was responsible for the appearance of inosinic acid in muscle and for at least a portion of ammonia liberated during contraction. He showed not only a marked specificity for deamination of 5 -AMP but also provided the first clue that muscle adenylic acid (5 -AMP) and yeast adenylic acid (3 -AMP) were different compounds. Initial evidence for guanine and adenosine aminohydrolase including aspects of the specificity were also described by Schmidt 16). Additional details regarding development of interest in purine aminohydrolases are available in several excellent reviews 17-20). 

Since guanine aminohydrolase catalyzes the deamination of thioguanine and 8-azaguanine thereby destroying their anti-neoplastic effects, Baker and his colleagues have prepared a series of active site directed irreversible inhibitors to block the enzyme in tumor tissue (193). The most effective inhibitor, 9-(4-methoxy phenyl)guanine, effected a 50 inhibition at 0.38 nM in the presence of 13.3 juM substrate (194). 

Purines and pyrimidines in excess of cellular requirements can be degraded. The extent of degradation depends on the organism. Humans cannot degrade purines beyond uric acid because we lack the enzyme uricase, which splits the purine ring to form allantoin. In humans excess AMP is deaminated to IMP by the action of a specific deaminase. IMP is then hydrolyzed by 5 -nucleotidase to form inosine. Inosine and guanine are oxidized to urate as follows ... 

In mammalian genomes, some cytosine residues of the CpG (cytosines adjacent to guanines) sequences in DNA are methylated, forming 5-methylcytosine. Deamination of 5-methylcytosine, however, yields thymine, a normal base component of DNA. In single-stranded DNA, this is a challenging problem as cells are not able to determine that this thymine is abnormal. In double-stranded DNA, however, deamination of the 5-methylcytosine in a methylated C G base pair yields a T G mismatch. Cells are therefore able to distinguish the thymine in a T G mismatch as... 

Guanase catalyzes the hydrolytic deamination of guanine to xanthine and ammonia. Its activity in serum is strongly elevated in patients with liver disease. 

Figure 10.7 Schematic representation of the formation and fate of IMP. Formation of IMP is catalyzed by the enzyme hypoxanthine/guanine phosphoribosyl tranfer-ase (1) from the substrate hypoxanthine (Hypo) and phosphoribosyl pyrophosphate (PRibPP). IMP is shown undergoing several reactions the first (2) is catalyzed by 5 -nucleotidase to form inosine (INO) and orthophosphate (Pj) the other (3) is a two-step reaction catalyzed by sAMP synthetase to form adenylosuccinate (sAMP) and (4) by the enzyme sAMP lyase to convert sAMP to AMP and fumarate. Finally, (3) the deamination of AMP to IMP and NHa is catalyzed by AMP deaminase.

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