Catabolism of purine nucleotides

Pathways for the formation of uric acid from purine nucleotides. [Reproduced with permission from G. Zubay, Biochemistry, 2nd ed. New York (Macmillan 1988). 1988 by Macmillan Publishing Company.] 

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FIGURE 22-45 Catabolism of purine nucleotides. Note that primates as uric acid from purine degradation. Similarly, fish excrete much more... 

Figure 25-18 Pathways of catabolism of purine nucleotides, nucleosides, and free bases. Spiders excrete xanthine while mammals and birds excrete uric acid. Spiders and birds convert all of their excess nitrogen via the de novo pathway of Fig. 25-15 into purines. Many animals excrete allantoin, urea, or NH4+. Some legumes utilize the pathway marked by green arrows in their nitrogen transport via ureides.

The detailed mechanism of myocardial protection via PC is not fully understood yet. Many pathways have been proposed and include myocardial stunning, synthesis of heat-shock proteins, involvement of G-proteins, and nitric oxide production [3-5]. The generally accepted model is that the ischemic phase leads to enhanced catabolism of purine nucleotides, resulting in a high level of adenosine. These activate PKC and a cascade of signaling steps leading to activation of MAP, MAPK and MAPKK, culminating in a marked effect on ATP-dependent channels [3,4,6, ]. 

Hypoxanthine is also a product of catabolism of purine nucleotides (Figure 22.7). Hypoxanthine can be converted to xanthine by the enzyme xanthine oxidase in the reaction that follows ... 

Figure 22.7 Catabolism of purine nucleotides to uric acid. 

CATABOLISM OF PURINE NUCLEOTIDES III. Breakdown of Uric Acid... 

The conventional pathway for the formation of ALN and ALA in animals and microbes involves the oxidative catabolism of purine nucleotides [Eq. (1)]. 

This enzyme returns the major products of purine nucleotide catabolism to nucleotide forms. 

Adenine phosphoribosyltransferase catalyzes the conversion of adenine to AMP in many tissues, by a reaction similar to that of hypoxanthine-guanine phosphoribosyltransferase, but is quite distinct from the latter. It plays a minor role in purine salvage since adenine is not a significant product of purine nucleotide catabolism (see below). The function of this enzyme seems to be to scavenge small amounts of adenine that are produced during intestinal digestion of nucleic acids or in the metabolism of 5 -deoxy-5 -methylthioadenosine, a product of polyamine synthesis. 

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... 

Catabolism of the nucleotides (Figure 24-3, B) begins with removal of their ribose-linked phosphate, a process catalyzed by purine 5 -nucleotidase. Removal of the ribose moiety of inosine and guanosine by the action of purine-nucleoside phosphorylase forms hypoxanthine and guanine, both of which are converted to xanthme. Xanthine is converted to uric acid through the action of xanthine oxidase. 

Fig. 4. Possible pathways of purine nucleotide anabolism and catabolism. The heavy arrows indicate the normal routes of degradation in man. I = phosphoribosylpyrophosphate, II = phosphoribosylamine, III = inosinic acid, IV = xanthylic acid, V = adenyhc acid, VI = guanyhc acid VII = hypoxanthine, VIII = xanthine, IX — uric acid, and X = adenosine.

To maintain relatively constant internal purine nucleotide levels despite continual de novo synthesis and dietary intake, mammals catabolize and excrete excess purines as uric acid (man and higher primates) or allantoin (other mammals). Purine catabolism begins with conversion into either hypoxanthine or xanthine, both of which are then degraded to uric acid by xanthine oxidase. In most mammals, uric acid is further degraded to allantoin by urate oxidase. In parasitic protozoans and helminths there is no apparent catabolism of purines due to the lack of xanthine oxidase. 

FIGURE 23.23 The reactions of purine catabolism, (a) Purine nucleotides are converted to the free base and then to xanthine, (b) Catabolic reactions of xanthine. 

An increased production of uric acid can result from clinical conditions in which there is a rapid increase in the rate of degradation of purine nucleotides. This degradation occurs as a result of the turnover or breakdown of nucleic acids and soluble nucleotides in the cell often associated with breakdown of the cell itself. Examples of this would include the acute leukemias and hemolytic anemias (2). In addition, the degradation of purine nucleotides can occur as a result of alterations in the energy of the cell which enhance the breakdown of ATP. Examples of this might include starvation, muscular exertion, and hypoxia. In some of these latter conditions related to the catabolism of purine nucleoside triphosphates, there may also be compensatory increase in the rate or purine biosynthesis de novo related to the release of feedback inhibition at the level of PRPP synthetase and/or PRPP amidotransferase. 

The catabolism of pyrimidine nucleotides, like that of purine nucleotides (Chapter 10), involves dephosphorylation, deamination, and glycosidic bond cleavage. In contrast to purine catabolism, however, the pyrimidine bases are most commonly subjected to reduction rather than to oxidation. An oxidative pathway is found in some bacteria however. 

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. 

Excess purine nucleotides or those released from DNA and RNA by nucleases are catabolized first to nucleosides (loss of P.) and then to free purine bases (release of ribose or deoxyribose). Excess nucleoside monophosphates may accumulate when ... 

Allopurinol markedly reduces xanthine oxide catabolism of the purine analogs, potentially increasing active 6-thioguanine nucleotides that may lead to severe leukopenia. The dose of 6-MP or azathioprine should be reduced by at least half in patients taking allopurinol. 

Uric acid is the excreted end product of purine catabolism in primates, birds, and some other animals. A healthy adult human excretes uric acid at a rate of about 0.6 g/24 h the excreted product arises in part from ingested purines and in part from turnover of the purine nucleotides of nucleic acids. In most mammals and many other vertebrates, uric acid is further degraded to al-lantoin by the action of urate oxidase. In other organisms the pathway is further extended, as shown in Figure 22-45. 

Allantoin is the excretory product in most mammals other than primates. Most fish hydrolyze allantoin to allantoic acid, and some excrete that compound as an end product. However, most continue the hydrolysis to form urea and glyoxylate using peroxisomal enzymes.336 In some invertebrates the urea may be hydrolyzed further to ammonia. In organisms that hydrolyze uric acid to urea or ammonia, this pathway is used only for degradation of purines from nucleotides. Excess nitrogen from catabolism of amino acids either is excreted directly as ammonia or is converted to urea by the urea cycle (Fig. 24-10). 

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