Hypoxanthine catabolism

Figure 34-8. Formation of uric acid from purine nucleosides byway of the purine bases hypoxanthine, xanthine, and guanine. Purine deoxyribonucleosides are degraded by the same catabolic pathwayand enzymes,all of which existin the mucosa of the mammalian gastrointestinal tract.

Purine catabolism to uric acid and salvage of the poime bases hypoxanthine (derived from adenosine) and guanine are shown in 1-18-5. 

Anabolic and catabolic pathways are involved in the metabolism of thiopurines (Fig. 2) (90,91,92). The enzyme hypoxanthine guanine phosphoribosylferase, responsible for bio-activation of thiopurines, converts 6-MP into 6-thioinosine monophosphate. 

As indicated in Fig. 25-18, free adenine released from catabolism of nucleic acids can be deaminated hydrolytically to hypoxanthine, and guanine can be deaminated to xanthine.328 The molybdenum-containing xanthine oxidase (Chapter 16) oxidizes hypoxanthine to xanthine and the latter on to uric acid. Some Clostridia convert purine or hypoxanthine to xanthine by the action of a selenium-containing purine hydroxylase.3283 Another reaction of xanthine occurring in some plants is conversion to the trimethylated derivative caffeine. 328b One of the physiological effects of caffeine in animals is inhibition of pyrimidine synthesis.329 However, the effect most sought by coffee drinkers may be an increase in blood pressure caused by occupancy of adenosine receptors by caffeine.330... 

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. 

Inosine formed by either route is then phosphorolyzed to yield hypoxanthine. Although, as we have previously seen, much of the hypoxanthine and guanine produced in the mammalian body is converted to IMP and GMP by a phosphoribosyltransferase, about 10% is catabolized. Xanthine oxidase, an enzyme present in large amounts in liver and intestinal mucosa and in traces in other tissues, oxidizes hypoxanthine to xanthine, and xanthine to uric acid (see fig. 23.20). Xanthine oxidase contains FAD, molybdenum, iron, and acid-labile sulfur in the ratio 1 1 4 4, and in addition to forming hydrogen peroxide, it is also a strong producer of the superoxide anion 02, a very reactive species. The enzyme oxidizes a wide variety of purines, aldehydes, and pteridines. 

Figure 2.3(D). Uricogenesis during alanine catabolism and gluconeogenesis in avian liver. Some abbreviations are as in figure 2.3(C). 1 C refers to one-carbon units MDH, malate dehydrogenase XDH, xanthine dehydrogenase PRPP, phosphoribosylpyrophosphate IMP, inosoine monophosphate ino, inosine hyp, hypoxanthine xan, xanthine.

The xanthine oxidoreductases are large, complex molybdo-flavoproteins with roles in the catabolism of purines, for example, oxidizing hypoxanthine to xanthine and xanthine to uric acid (equation 9). Xanthine oxidase can also catalyze the reduction of nitrate to nitrite (or in the presence superoxide, peroxynitrite) and the reduction of nitrite to nitric oxide. Peroxynitrite, a powerfiil and destructive oxidant, has been implicated in diseases such as arthritis, atherosclerosis, multiple sclerosis, and Alzheimer s and Parkinson s diseases. The microbicidal role of milk and intestinal xanthine oxidase may also involve the generation of peroxynitrite in the gut. The high levels of the enzyme in the mammary glands of pregnant... 

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... 

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. 

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... 

Inhibition of Xanthine Oxidase Uric acid, the end product of purine catabolism in humans, is formed by the serial oxidation of hypoxanthine and of xanthine, catalyzed by xanthine oxidase. 

In most cells, more than 90% of the oxygen utilized is consumed in the respiratory chain that is coupled to the production of ATP. However, electron transport and oxygen utilization occur in a variety of other reactions, including those catalyzed by oxidases or oxygenases. Xanthine oxidase, an enzyme involved in purine catabolism (Chapter 27), catalyzes the oxidation of hypoxanthine to xanthine, and of xanthine to uric acid. In these reactions, reducing equivalents are transferred via FAD, and Fe and Mo " ", while the oxygen is converted to superoxide anion (O2) ... 

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.

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 shows pathways of purine catabolism leading to uric acid. As seen in the figure, AMP and GMP can both be hydrolyzed from their phosphates by nucleotidase, ultimately yielding the bases hypoxanthine and xanthine, respectively. 

Figure 11.1 shows pathways of purine catabolism leading to uric acid. As seen in the figure, AMP and GMP can both be hydrolyzed from their phosphates by nucleotidase, ultimately yielding the bases hypoxanthine and xanthine, respectively. Hypoxanthine is converted to xanthine by xanthine oxidase and xanthine is converted to uric acid, also by xanthine oxidase. In addition, AMP can be degraded first in a deamination to form IMP, which loses its phosphate to become inosine. Inosine, in turn, is converted to hypOxanthine. 

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. 

Allopurinol decreases the formation of uric acid, by inhibiting xanthine oxidase, a key enzyme in the catabolism of oxypurines (hypoxanthine and xanthine) to uric acid. The rate of formation of uric acid is therefore decreased in a dose-dependent manner. 

Allopurinol facilitates the incorporation of xanthine and hypoxanthine into nucleic acids, lowering the substrates for catabolism. In addition, the decrease in xanthine metabolism facilitates a negative feedback on purine synthesis. 

Xanthine oxidase and xanthine dehydrogenase represent different forms of the same gene product. Xanthine dehydrogenase and xanthine oxidase are interconvertable thus, these two enzyme forms and their reactions often are referred to as xanthine oxidoreduotase. Xanthine oxidase is the rate-limiting enzyme in purine catabolism of hypoxanthine to uric acid via xanthine. Both xanthine oxidase and xanthine dehydrogenase play important roles in the ... 

In its role in purine catabolism, XnDH catalyzes sequential hydroxylation of the C-2 and C-8 atoms of hypoxanthine, converting it first to xanthine and then to uric acid (eqn (7.1), keto forms shown). In humans, enzyme deficiency is associated with xanthinuria types I and II, the symptoms of which include urinary tract infections, myopathy, arthritis, arthralgia, kidney stones and acute renal failure, while over-activity causes hyperuricemia and the deposition of urate salts in the joints leading to gout. ... 

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