Purine incorporation into nucleic acids

Not all analogues become active against cancer cells through incorporation into nucleic acid. Some analogues block the synthesis of normal purine and pyrimidine nucleotides for example, 8-azaguanine blocks guanosine monophosphate (GMP) synthesis and 6-mercaptopurine inhibits adenosine monophosphate (AMP) syn-thesis. 

The subject of the incorporation of anticancer agents into macromolecules [13] and other compounds [336] has been reviewed. A number of purine analogues are incorporated into nucleic acid, but the incorporation of these compounds requires that they be anabolized to nucleoside mono-, di-, and triphosphates, and it is difficult to separate the metabolic effects of the nucleoside phosphates from the metabolic effects of the fraudulent polynucleotides. 

Dietary purines are not an important source of uric acid. Quantitatively important amounts of purine are formed from amino acids, formate, and carbon dioxide in the body. Those purine ribonucleotides not incorporated into nucleic acids and derived from nucleic acid degradation are converted to xanthine or hypoxanthine and oxidized to uric acid (Figure 36-7). Allopurinol inhibits this last step, resulting in a fall in the plasma urate level and a decrease in the size of the urate pool. The more soluble xanthine and hypoxanthine are increased. 

B-4) Mercaptopurine is an antitumor drug that looks like the purine adenine and acts partly by interfering with its incorporation into nucleic acids. 

The anabolites of purine and pyrimidine antagonists may be incorporated into nucleic acids. In this event, port of their antitumor effect might result from malfunction of further macromolecular. synthesis because of the abnormal nucleic aeids. ... 

Adenosine was shown to be incorporated into nucleic acid purines, but to only about half the extent of adenine itself (L2). The incorporation of guanosine was also studied and here again the guanine derivative was a poorer precursor than the adenine derivative, but the utilization of guanosine was considerably greater than that of the aglycone (L22). The administration of the adenine nucleotides revealed that these compounds, whether as the 3 isomer or the 5 isomer, were poorer precursors than the free base adenine (Wl). With all nucleotides studied, the incorporation of the 5 isomer was less extensive than of the 3 isomer (R9). Roll et al. have shown that guanine nucleotides are considerably... 

From the species names, one may recognize some of the various participants in purine metabolism. The important purines guanine (Gua) and adenine (Ade) are both synthesized from inosine monophosphate (IMP). They may then be derived to (d)GTP and (d)ATP, respectively, prior to incorporation into nucleic acids like DNA and RNA. This simple explanation betrays the true complexity of purine metabolism, and elucidating the properties of such complex systems depends on sophisticated computational tools, which we describe presently. 

Both, purine and pyrimidine bases incorporated into nucleic acids, or in synthetic nucleic acid analogs, are able to bind specifically different metal ions [138]. For example, thymine yields a thymine-Hg -thymine complex, while cytosine forms specifically a cytosine-Ag -cytosine complex. Such properties of the nucleic acids were utilized to develop QDs-based Hg -ion and Ag + -ion sensors, with differentsized QDs being implemented for the multiplexed analysis of Hg and Ag + [139]. Two different-sized CdSe/ZnS QDs were modified with nucleic acids of specific ionbinding properties blue-emitting QDs ()iem = 560 nm) were functionalized with the thymine-rich nucleic acid (16) that binds Hg + -ions, while the red-emitting QDs (Xem = 620nm) were functionalized with the cytosine-rich nucleic acid (17) that associated with Ag + -ions (Figure 6.9a). The formation of Hg -modified complexes... 

Pyrimidine 1,3-diazine, a heterocyclic compound, consisting of a six-membered ring with 2 nitrogen atoms (Fig.l), M, 80.1, m.p. 20-22°C, b.p. 124°C. The P. ring system is present in many natural compounds, e. g. antibiotics (nucleoside antibiotics), pterins, purines and vitamins, it is especially important in the pyrimidine bases. Cytosine (see). Uracil (see) and Thymine (see), which are constituents of nucleic acids. Pyrimidine itself does not occur naturally. Pyrimidine analogs (see) can also be incorporated into nucleic acids. 

The cytokinins themselves cannot be incorporated into nucleic acids, but adenine residues in tRNA can be converted to cytokinin moieties. Roughly 0.05 to 0.1% of tRNA bases are estimated to be cytokinins. 6-(3-Methyl-2-butenylamino)purine, 6-(4-hydroxy-3-methyl-2-czs-butenyl-... 

The inhibitory effects of allopurinol and oxipurinol on purine and pyrimidine biosynthesis in human fibroblasts could be explained by formation of their respective ribonucleotides either by HGPRTase (allopurinol) or OPRTase (oxipurinol). The effects of allopurinol-1-ribonucleoside are hardly to be explained. Theoretically the allopurinol-1-ribonucleoside can be converted either to the free base (catalyzed by a purine nucleoside phosphorylase) or to allopurinol-1-ribonucleotide (catalyzed by a nucleoside kinase). According to Utter et al. (4) there seems however to be a lack of kinases in mammals which effectively phosphorylate inosine. Furthermore, indirect experiments of Elion et al. (5), where no detectable nucleotide formation or incorporation into nucleic acids was observed in vivo with Hc-allopurinol would support this. Nevertheless, our results would claim for a direot conversion of allopurin-ol-1-ribonucleoside to allopurinol-1-ribonucleotide in human fibroblast, at least at doses from 10 5 -to 10-3 M. Otherwise we would have to explain the inhibitory effects of allopurinol-1-ribonucleoside by direct influences on purine synthesis, for the other possibility theoretical-... 

Adenine is inert in the nucleoside phosphorylase systems of both mammalian tissues and microorganisms, but isotopically labeled adenine is effectively incorporated into nucleic acid purines, both in rats " and in yeast.This poses a question as to the possible role of nucleoside phosphorylase in polynucleotide synthesis. It has been suggested that hypoxanthine or guanine nucleosides (or nucleotides) are synthesized first. Then an exchange reaction with free adenine (or a derivative) might occur, For example, adenine might react with inosine to form adenosine and hypoxanthine. Some known exchange reactions are discussed below. 

III. Incorporation of Preformed Purine Compounds into Nucleic Acids.413... 

The fate of other purine-ribose compounds was studied in the rat and it was found that C Mabeled adenosine (211) and adenylic acid (212) were utilized for the s3Tithesis of RNA adenine and guanine, but to a much smaller extent than adenine (191). Similarly, growing yeast utilized the purine base, adenine, far more readily than the corresponding nucleoside or nucleotide (195). It was believed that the ribose derivatives were poorly utilized because they were first cleaved to free adenine, which was incorporated subsequently into polynucleotides. It is curious that the attachment of ribose or a ribose pho hate moiety to adenine or guanine did not facilitate their incorporation into nucleic acids. In contrast, inosine, the ribonucleoside of hypoxantbine, was utilized considerably by the rat as a nucleic acid precursor (211) the corresponding deoxyriboside, deoxyinosine, was not (213). 

Seasonal variations in the metabolic fate of adenine nucleotides prelabelled with [8—1-4C] adenine were examined in leaf disks prepared at 1-month intervals, over the course of 1 year, from the shoots of tea plants (Camellia sinensis L. cv. Yabukita) which were growing under natural field conditions by Fujimori et al.33 Incorporation of radioactivity into nucleic acids and catabolites of purine nucleotides was found throughout the experimental period, but incorporation into theobromine and caffeine was found only in the young leaves harvested from April to June. Methy-lation of xanthosine, 7-methylxanthine, and theobromine was catalyzed by gel-filtered leaf extracts from young shoots (April to June), but the reactions could not be detected in extracts from leaves in which no synthesis of caffeine was observed in vivo. By contrast, the activity of 5-phosphoribosyl-1-pyrophosphate synthetase was still found in leaves harvested in July and August. 

One of the first studies that indicated the possible interference of ametbopterin and aminopterin with purine synthesis was the demonstration by Skipper et al. (S21) that administration of these compounds to mice inhibited the incorporation of labeled formate into nucleic acid purines. Ametbopterin (4-amino-A -methyl-pteroylglutamic acid) has produced some inhibition of uric acid synthesis during the use of this compound for treatment of leukemia (K15, E24). Another inhibitor of... 

By competing with PABA, the sulfonamides inhibit the synthesis of folic acid, which is essential for the production of purines by bacteria and their ultimate synthesis of nucleic acids. They are also incorporated into folic acid. 

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