Xanthine breakdown

Allopurinol, a xanthine-oxidase inhibitor, may decrease tissue urate deposits in patients who are overproducers of uric acid, i.e. patients with primary hypemricaemia, in myeloproliferative neoplastic diseases and in hyperuricaemia resulting from tissue breakdown after cancer chemotherapy or radiation therapy. Allopurinol may also be recommended, in certain circumstances, in undersecre-tors of uric acid. 

B. Allopurinol inhibits xanthine oxidase, the enzyme involved in the conversion of hypoxanthine and xanthine to uric acid. It has no known ability to increase uric acid synthesis markedly (A), inhibit reabsorption (C), or impair uric acid breakdown (D). 

Most of the free purines derived from the breakdown of DNA, RNA, and nucleotides in the diet are catabolized to xanthine and then to uric acid in the gut mucosa. The AMP and GMP biosynthesized in the body can also be bmken down to free purines, such as adenine, guanine, and hypoxanthine. These purines, in contrast to those derived frcim the diet, are largely reused for the synthesis of ATP and GTP- They are first converted back to AMP or GMP in a pathway of reutiliza-lion called the purine salvage pathway. For example, adenine phosphoribosyl-transferase (PRPP) catalyzes the conversion of adenine to AMP. Here, PRPP serves as the source of the phosphoribose group. Pyrophosphate is a product of the reaction. 

Uric acid is the major product of catabolism of purine nucleosides adenosine and guanosine. Hypoxanthine and xanthine are intermediates along this pathway (Fig. 2). Under normal conditions, they reflect the balance between the synthesis and breakdown of nucleotides. Levels of these compounds change in various situations (e.g., they decrease in experimental tumors) when synthesis prevails over catabolism, and are enhanced during oxidative stress and hypoxia. Uric acid serves as a marker for tubular... 

Figure 6 is a metabolic map of nucleoprotein catabolism, and Table 6 shows some of the components that can be recovered from scrapings of normal skin, from callus, and from psoriatic scales. In conjunction with the preceding it shows that about 5% of the RNA and less than 1% of the DNA is left in the normal horny layer while up to one-third of the RNA and DNA is still present in the cells of the parakeratotic horny layer of psoriasis. Xanthine and hypoxanthine can be found in psoriatic scales and presumably result from catabolism of nucleic acid purines. Uric acid, although present in the scales, probably comes from the blood, since xanthine oxidase has not been found in human epidermis (B15, B17). Pyrimidine breakdown products have not been found. This might... 

Whole brain homogenates have been found to contain very low levels or to be devoid of either of the molybdenum hydroxylases [92, 107, 108, 120]. However, more specific assays for xanthine oxidase gave values of 2-20 nmol xanthine transformed/mg per h for homogenates of cortex or whole brain from mouse, rat, guinea-pig, rabbit and cow [46, 121], Less activity was detected in the cerebellum [121] and, again, the cranial capillary endothelial cells were found to be enriched in xanthine oxidase [46], Brain hypoxanthine concentrations are reported to rise during ischaemia due to increased ATP breakdown, and Betz [46] proposed that brain capillaries may be susceptible to damage... 

Neither methotrexate nor its microbial breakdown product, APA, is a substrate for xanthine oxidase [6, 215], although this may be more a function of the 2,4-diaminopteridine moiety, which itself is refractory to xanthine oxidase [204], rather than the glutamic acid residue. In fact, methotrexate is a potent competitive inhibitor of this enzyme, with a K value of around 25 fiM [218,219]. There is considerable controversy as to whether folic acid, a substituted 2-aminopteridin-4-one, is also an inhibitor of xanthine oxidase. It is not oxidized at carbon 7, unlike the parent compound, which is a poor substrate [204]. However, some workers have shown that folic acid is an extremely potent competitive inhibitor of xanthine oxidase, some 10-times more effective in vitro than allopurinol, whereas other reports claim that the inhibition is due to the contaminant 2-amino-4-oxopteridine-6-aldehyde (27), which is a photolytic breakdown product of folic acid [4, 171, 172, 218-220]. 

Uric acid that is produced in man is essentially the product of the action of the enzyme xanthine oxidase on xanthine and hypoxanthine. A tiny amount of uric acid may be ingested as part of the diet, but the great bulk is the result of the action of this enzyme on these two purines. These purines are themselves produced either as a result of the breakdown of cellular material in toto, the turnover of nucleic acids in the cells, or as a result of the intermediary metabolism of various purine nucleotide derivatives. These latter compounds are active in the flow of energy, in methyl group transfer reactions, and as part of the functional molecule of many vitamins. There is direct and indirect evidence that some of the uric acid derives from all these sources. Essentially this evidence consists of the demonstration that other parts of the nucleie acids are found in the urine, such as pyrimidine breakdown products (P9) and methylated purines, which are found only in nucleic acids. There is also isotopic evidence that some labeled purines appear in the urine too quickly after administration of radioactive precursors... 

Not only is uric acid found in the urine and the serum, but small amounts of its precursors xanthine and hypoxanthine and a variety of other purines are found in the serum and in the urine. Many of these are breakdown products of the ribonucleic acids which contain methylated purines. When these macromolecules are broken down the methylated purines are not reutilized but are excreted (B13). In addition, a large number of purine derivatives such as theobromine and caffeine are found in various foods. 

The breakdown of xanthine by Clostridium addiurici and C. cylindro-sporum is of interest not only because this purine can be the sole energy source of these microorganisms, but also because many of the intermediates of this pathway resemble dephosphoribosylated intermediates of the pathway of purine biosynthesis de novo. 

Purine bases are a group of compounds found in plants and animals —they include nucleic acids. Their biosynthesis is complex with numerous non-amino-acid precursors (Samuelsson 1992). Xanthine, an oxidised purine that occurs as a breakdown product of nucleic acid metabolism, is itself oxidised in the body to uric acid. Xanthine consists of two fused ring systems each containing two nitrogen atoms. 

The rapid endogenous breakdown of tissue nucleic acids and nucleotides to form purine bases in homogenates has also been observed by G. R. Greenberg and by Richert, Edwards, and Westerfeld. The latter investigators have noted that, in liver homogenates of species of animals containing xanthine oxidase, up to one-half of the initial respiration of the tissue may result from the oxidation of purine bases. It would, therefore, be difficult to study specifically the synthesis of purines de novo... 

The main end product of purine—adenine, guanine and xanthine—metabolism in birds, reptiles, and man, which is excreted in the urine. Uric acid is formed from purines consumed in the diet, and from body purines derived from the breakdown of nucleic acids. Mammals other than man further metabolize uric acid to allantoin, which is excreted in the urine. However, man lacks the enzyme, urate oxidase, necessary for this conversion. Therefore, about 0.5 to 1.0 g of uric acid is lost in the urine each day. A high level of uric acid in the blood is associated with the development of gout. In addition, uric acid may form kidney stones, especially in individuals suffering from gout. 

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