Purines/purine nucleotides metabolism

Box 20.2 Deficiencies or low activities of enzymes involved in purine nucleotide metabolism... 

Severe combined immunodeficiency arises from inhibition of lymphocyte proliferation because B and T cells are particularly sensitive to allosteric inhibition of which of the following enzymes of purine nucleotide metabolism ... 

The answer is D. Impaired immune function in severe combined immunodeficiency (SCID) is the direct result of blocked DNA synthesis due to inadequate supplies of de-oxyribonucleotides in B and T cells. This effect arises by dATP-induced allosteric inhibition of ribonucleotide reductase, which catalyzes reduction of the 2 -hydroxyl groups on ADP and GDP to form dADP and dCDP. The ultimate cause of many cases of SCID is adenosine deaminase deficiency, which leads to accumulation of dATP and consequent inhibition of ribonucleotide reductase. Although the other enzymes mentioned are also involved in purine nucleotide metabolism, their deficiencies do not lead to SCID. 

The molecular basis for the therapeutic effects of the purine analogs is unknown. Intracellular 6-thioguanine causes inhibition of purine nucleotide metabolism and DNA synthesis and repair, resulting in inhibition of cell division and proliferation. 

Uric acid is an intermediate in purine nucleotide metabolism (Figure 22.7) and is quite insoluble in water. Consequently, increasing concentrations of it causes it to precipitate as crystals of sodium urate, and cause the painful condition of gout. 

Konigk, E. (1978) Purine nucleotide metabolism in promastigotes of Leishmania tropica inhibitory effect on allopurinol and analogues of purine nucleosides. Tropenmed. Parasitol. 29 435-438. 

Since the two isozymes of adenylosuccinate synthetase differ so markedly, changes in the relative amounts of the two could drastically affect the regulation of the reaction they catalyze, and therefore the direction of purine nucleotide metabolism. Determination of this ratio could be a useful indicator of the relative importance of the biosynthetic and the cyclic aspects of the adenine nucleotide interconversion pathway in different tissues or under different metabolic conditions. 

EFFECTS OF FRUCTOSE ON PURINE NUCLEOTIDE METABOLISM IN ISOLATED RAT HEPATOCYTES... 

In recent years it became apparent that fructose metabolism in the liver tissue has considerable effects on purine nucleotide metabolism. There is ample evidence that fructose metabolism is associated with acceleration of nucleotide degradation (1-5) and evidence is accumulating (6-8), indicating an acceleration effect of fructose also on purine synthesis. 

The present investigation was undertaken in an attempt to further clarify the effects of fructose on purine nucleotide metabolism. Isolated rat hepatocytes were chosen as a model system, since they allow the study of each pathway of purine metabolism separately and without interference from other tissues. 

Purine Nucleotide Metabolism and Nucleotide Pool Sizes in Synchronized Lymphoma L5178Y Cells. Cancer Res. 33 2425 (1973). 

Information on cellular metabolic organization of caffeine biosynthesis and catabolism links to purine nucleotide metabolism, intercellular translocation, and accumulation mechanisms at specific cellular sites, such as chloroplasts and vacuoles, have yet to be fully revealed. Cell-, tissue-, and organ-specific synthesis and possibly catabolism of purine alkaloids may be regulated by unique and unknown developmental- and environmental-specific control mechanisms. A great deal of fascinating purine alkaloid biology in plants still remained to be discovered. 

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. 

Volume LI. Purine and Pyrimidine Nucleotide Metabolism Edited by Patricia A. Hoffee and Mary Ellen Jones... 

Deficiency of the muscle-specific myoadenylate deaminase (MADA) is a frequent cause of exercise-related myopathy and is thought to be the most common cause of metabolic myopathy. MADA catalyzes the deamination of AMP to IMP in skeletal muscle and is critical in the purine nucleotide cycle. It is estimated that about 1-2% of all muscle biopsies submitted to medical centers for pathologic examination are deficient in AMP deaminase enzyme activity. MADA is 10 times higher in skeletal muscle than in any other tissue. Increase in plasma ammonia (relative to lactate) after ischemic exercise of the forearm may be low in this disorder, which is a useful clinical diagnostic test in patients with exercise-induced myalgia... 

Sterol biosynthesis Bile acid biosynthesis C2rSteroid hormone metabolism Androgen and estrogen metabolism Nucleotide Metabolism Purine metabolism Pyrimidine metabolism Nucleotide sugar metabolism Amino sugar metabolism Amino Acid Metabolism Glutamate metabolism Alanine and aspartate metabolism Glycine, serine, and threonine metabolism... 

These one-carbon groups, which are required for the synthesis of purines, thymidine nucleotides and for the interconversion some amino acids, are attached to THF at nitrogen-5 (N5), nitrogen-10 (N10) or both N5and N10. Active forms of folate are derived metabolically from THF so a deficiency of the parent compound will affect a number of pathways which use any form of THF. 

The pyrimidine nucleotides (predominantly UMP, CMP, and dTMP) are hydrolysed to their respective bases (uracil, cytosine, and thymine) by reactions similar to those for metabolism of purine nucleotides. The pathways of... 

Figure 2.1. Cellular metabolism of purine nucleotides. The meaning of the numbers over the arrows is explained on the next page. 

In addition to the enzymes that catalyse the formation of nucleotides and polynucleotides, a large number of catabolic systems exist which operate at all levels of the internucleotide pathways. The ribonucleases and deoxyribonucleases that degrade polynucleotides are probably not significantly involved in purine analogue metabolism, but the enzymes which dephosphorylate nucleoside 5 -monophosphates are known to attack analogue nucleotides and may be of some importance to their in vivo activity. Phosphatases of low specificity are abundant in many tissues [38], particularly the intestine [29]. Purified mammalian 5-nucleotidases hydrolyse only the nucleoside 5 monophosphates [28] and... 

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]. 

Thioguanine (6-TG) also inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway. Various metabolic lesions result, including inhibition of purine nucleotide interconversion decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis interference with the formation of DNA and RNA and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia. 

Free purine and pyrimidine bases are constantly released in cells during the metabolic degradation of nucleotides. Free purines are in large part salvaged and reused to make nucleotides, in a pathway much simpler than the de novo synthesis of purine nucleotides described earlier. One of the primary salvage pathways consists of a single reaction catalyzed by adenosine phosphoribosyltransferase, in which free adenine reacts with PRPP to yield the corresponding adenine nucleotide ... 

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