Guanine degradation

Cleavage at A or G If the DNA is first treated with acid, dimethyl sulfate methylates adenine at the 3-position as well as guanine at the 7-position (not shown). Subsequent reaction with OH and piperidine triggers degradation and displacement of the methylated A or G purine base and strand scission, essentially as indicated here for reaction of dimethyl sulfate with guanine. 

One of the steps in the metabolic degradation of guanine is hydrolysis lo give xanthine. Propose a mechanism. 

The different possible adducts formed between mitomycin C and DNA have been isolated by degradation of DNA after in vitro alkylation/crosslinking reactions and structurally characterized. Monoadduct 21 (Scheme 11.3), derived from alkylation at C-l only [53], and monoadducts 22 [54] and 23 [55, 56] (derived from C-10 alkylation by 16 at N-7 or N-2 of guanine, respectively) have been isolated, together with bisadducts 24 [57] and 25 [58], derived from interstrand and intrastrand crosslinks, respectively, and adduct 26 [59], formed by addition of a molecule of water to C-10 instead of the second guanine. All of these adducts have also been isolated from DNA after in vivo crosslinking [60, 61]. 

Figure 34-8. Formation of uric acid from purine nucleosides byway of the purine bases hypoxanthine, xanthine, and guanine. Purine deoxyribonucleosides are degraded by the same catabolic pathwayand enzymes,all of which existin the mucosa of the mammalian gastrointestinal tract.

Schimanski, A., Ereisinger, E., Erxleben, A. and Lippert, B. (1998) Interactions between [AuX4] (X = Cl, CN) and cytosine and guanine model nucleobases salt formation with (hemi-) protonated bases, coordination, and oxidative degradation of guanine. Inorganica Chimica Acta, 283, 223. 

Nucleic acid degradation in humans and many other animals leads to production of uric acid, which is then excreted. The process initially involves purine nucleotides, adenosine and guanosine, which are combinations of adenine or guanine with ribose (see Section 14.1). The purine bases are subsequently modified as shown. 

The nucleotides are among the most complex metabolites. Nucleotide biosynthesis is elaborate and requires a high energy input (see p. 188). Understandably, therefore, bases and nucleotides are not completely degraded, but instead mostly recycled. This is particularly true of the purine bases adenine and guanine. In the animal organism, some 90% of these bases are converted back into nucleoside monophosphates by linkage with phosphori-bosyl diphosphate (PRPP) (enzymes [1] and [2]). The proportion of pyrimidine bases that are recycled is much smaller. 

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. 

Since chemistry of pterines and purines has been already reviewed (42,48,491), only recent studies will be described here. Guanine (93) was prepared by reaction of 4-hydroxy-2,5,6-triaminopyrimidine sulfate (588 see Scheme 73) with HCONH2 with removal of H2O from the reaction system in an excellent yield (492). Also, irradiation of oxygenated aqueous solutions of 6-mercaptopurine with near-UV light gave hypoxanthine (92) as a minor product (< 10%) together with purine-6-sulfinate (589). It also arises from degradation of purine-6-sulfonate obtained from photooxidation of the sulfinate (589) (493). 

There are no available data on the formation of hydroperoxides derived from DNA within cells. This is likely explained, at least partly, by the fact that DNA is a poorer target than proteins for OH radical as observed upon exposure of mouse myeloma cells to ionizing radiation . However, indirect evidence for DNA peroxidation within cells may be inferred from the measurement of final degradation products that may derive from thymine and guanine hydroperoxidation as the result of oxidation reactions mediated by OH radical and O2, respectively (Sections n.A.2 and n.E.2). It may be pointed out that the measurement of oxidized bases and nucleosides within DNA has been the subject of intense research during the last decade and accurate methods are now available . This includes DNA extraction that involves the chaotropic Nal precipitation step and the use of desferrioxamine to chelate transition metals in order to prevent spurious oxidation of overwhelming nucleobases to occur . HPLC coupled to electrospray ionization... 

Procarbazine (Matulane) may autooxidize spontaneously, and during this reaction hydrogen peroxide and hydroxyl free radicals are generated. These highly reactive products may degrade DNA and serve as one mechanism of procarbazine-induced cytotoxicity. Cell toxicity also may be the result of a transmethylation reaction that can occur between the A-methyl group of procarbazine and the N7 position of guanine. 

The effect of photodynamic degradation on the viscosity of DNA132 was shown to be the result initially of single chain breaks, followed eventually by double chain scission this is in agreement with the idea that guanine oxidation is the cause of the viscosity change. 

Purines that result from the normal turnover of cellular nucleic acids can be reconverted into nucleoside triphosphates and used by the body. Thus, they are "salvaged" instead of being degraded to uric acid. PRPP is the source of the ribose-phosphate, and the reactions are catalyzed by adenine phosphoribosyltransferase, and hypoxanthine-guanine phosphoribosyltransferase (HPRT). 

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