Purines normal metabolism

Antimetabolites interfere with normal metabolic pathways. They can be grouped into folate antagonists and analogues of purine or pyrimidine bases. Their action is limited to the S-phase of the cell cycle and therefore they target a smaller fraction of cells as compared with alkylating agents. 

Purines and Related Heterocycles Considerable research has been devoted to preparation of modified purines in the expectation that such compounds could act as antagonists to, or possibly false substrates for, those involved in normal metabolic processes. It is surprising to note the relatively small number of such compounds that have found clinical use. 

Because of the conflicting results, it seems necessary tentatively to accept the possibility that nucleic acid purines may be synthesized under normal metabolic conditions from preformed purines as well as from elementary precursors. The problem of ascertaining the role in normal metabolism of preformed purine compounds is difficult, since it is known that the mammalian organism is able to synthesize its own purines from simple metabolites and does not require dietary purines. Recent studies indicate that incompleted purine structures joined to ribose and phosphate are intermediates in purine synthetic reactions in vitro, and that... 

Uric acid is a normal product of metabolism. The chemistry of the purines, the uric acid syntheses of Baeyer and Fischer, Behrend and Roosen, and W. Traube, the chemistry of adenine, guanine, caffeine, and their relationships to uric acid, should be studied. 

Although demethylation, which occurs in the liver, is normally considered to be a catabolic process, it may result in conversion of an inactive form of a drug to the active form. Thus 6-(methylthio)purine (XXXIX) is demethylated by the rat to 6-mercaptopurine [205]. This demethylation occurs in the liver micro-somes and is an oxidative process which converts the methyl group to formaldehyde [204, 207]. The 1-methyl derivative of 4-aminopyrazolo[3,4-d] pyrimidine (XLI) is demethylated slowly, but 6-mercapto-9-methylpurine (XLII) not at all [208]. The A -demethylation of puromycin (XLlIl) [209, 210], its aminonucleoside (XLIV) [211], and a number of related compounds, including V-methyladenine and V,V-dimethyladenine, occurs in the liver microsomes of rodents [212]. In the guinea-pig the rate-limiting step in the metabolism of the aminonucleoside appears to be the demethylation of the monomethyl compound, which is the major urinary metabolite [213]. The relationship of lipid solubility to microsomal metabolism [214], and the induction of these demethylases in rats by pre-treatment with various drugs have been studied [215]. 

The reason for the selective toxicity of 6-mercaptopuiine remains to be established, but two factors may be of primary importance. 6-Mercaptopurine is anabolized primarily, if not exclusively, to the monophosphate level, and it is readily catabolized by xanthine oxidase, an enzyme that is low in most cancer cells compared to normal cells. Another factor that must be considered is the metabolic state of the target cells. Actively proliferating leukaemia cells are more sensitive to 6-mercaptopurine, as they are to all antimetabolites, than cells in the so-called Gq or stationary phase. Although this does not explain the difference between 6-mercaptopurine and other purine analogues, it may explain the ineffectiveness of 6-mercaptopurine against solid tumours, most of the cells of which are in the non-dividing state. 

Apparently the acceleration of de novo purine biosynthesis by orotic acid results from a release of feedback inhibition imposed by hepatic purine nucleotides. In a related study, it was found that orotic acid feeding can prevent hyperlipaemia, which normally follows the administration of Triton WR-1339, a surface active agent [152]. The influence of orotic acid on lipid metabolism can be readily shown by the fact that depression of serum lipoproteins and milk production were observed in lactating goats when an aqueous suspension of orotic acid was administered orally [164]. 

Gout results from hyperuricemia i.e. increased serum uric acid levels. Normal serum uric acid level is 1-5 mg/dl. Uric acid is formed in the metabolism of purine. When the blood levels of uric acid are high, it precipitates in joints, cartilage, kidney and subcutaneous tissues and leads to various signs and symptoms. Hyperuricemia is also seen in various leukemias, lymphomas... 

Folacin (folic acid) is involved in metabolism and in the biosynthesis of purines and pyrimidines. It is a very stable vitamin but does not occur naturally in feedstuffs. Instead it occurs in reduced forms as polyglutamates, which are readily oxidized. These forms are converted to folic acid in the body. Diets commonly contain sufficient folacin but this is not assured. Folacin is therefore usually included in the vitamin supplement added to poultry diets to ensure adequacy. A deficiency in young chicks or poults results in retarded growth, poor feathering and perosis. Coloured plumage may lack normal pigmentation, and a characteristic anaemia is also present. Cervical paralysis is an additional symptom in deficient turkeys. 

The so-called salvage pathways are available in many cells to scavenge free purine and pyrimidine bases, nucleosides, and mononucleotides and to convert these to metabolically useful di- and trinucleotides. The function of these pathways is to avoid the costly (energy) and lengthy de novo purine and pyrimidine biosynthetic processes. In some cells, in fact, the salvage pathways yield a greater quantity of nucleotides than the de novo pathways. The substrates for salvage reactions may come from dietary sources or from normal nucleic acid turnover processes. 

Levels of 8-OHdG have also been measured in human and rodent urine. Preliminary results indicate a trend towards lower levels in CGD patients than in normal control subjects [141], It is also reported that urinary 8-OHdG levels are higher in mice than in humans [142]. However, it is not known whether this product in human urine is derived exclusively from DNA via repair-enzyme processes Oxidation of free guanine, normal purine metabolism and/or dietary factors might contribute to urinary 8-OHdG. 

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