Uric acid, purine catabolism

The purine catabolic pathway appears in Figure 8,31, The end-product of purine cataboiism in primates, and in some other vertebrates, is uric acid, Purine catabolism differs in other species. Urate oxidase catalyzes the breakdown of uric acid to allantoin. Allantoin can be further broken down to produce urea and glyoxyJate, Allantoin is the purine excretory pixiduct in some mammals and reptiles. Urea is the purine excretory product in fish. Guanine is the purine excretory product in pigs and spiders. Uric acid is used for the packaging and excretion of waste N from amino acids in birds and some reptiles. 

Xanthine oxidase (XOD) is the key enzyme in purine catabolism. XOD catalyses the conversion ofhypoxan-thine to xanthine and of xanthine to uric acid, respectively. The uricostatic drug allopurinol and its major metabolite alloxanthine (oxypurinol) inhibit xanthine oxidase. 

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.

Humans catabolize purines to uric acid (pA 5.8), present as the relatively insoluble acid at acidic pH or as its more soluble sodium urate salt at a pH near neutrality. Urate crystals are diagnostic of gout. Other disorders of purine catabolism include Lesch-Nyhan syndrome, von Gierke s disease, and hypo-uricemias. 

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

For birds, insects, and reptiles, which have an egg stage during development, so that water availability is severely restricted, the synthesis of a highly soluble excretory product would have serious osmotic consequences therefore most of the ammonia is converted to the virtually insoluble uric acid (urate). This product can be safely retained in the egg or excreted as a slurry of fine crystals by the adult. In birds that nest colonially this can accumulate in massive amounts on islands off the coast of Peru cormorants have deposited so much that this guano (hence the name guanine) is collected for use as a fertiliser. Uric acid is less effective as an excretory product, since it has a lower nitrogen content than urea (33%) and is more expensive to synthesise (2.25 molecules ATP per atom of nitrogen). Mammals do produce uric acid but as a product of purine catabolism (see above). 

Isoprinosine is an immunostimulant dmg that increases natural killer cell cytotoxicity as well as to increase the activity of T-cells and monocytes. The drug has some clinical activity against viral encephalitis such as subacute sclerosing panencephalitis and severe manifestations of immunodeficiencies. Because the purine (inosine) moiety of isoprinosine is rapidly catabolized to uric acid it should be used with care in patients with a history of gout. 

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

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. 

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.

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... 

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). 

Another form of detoxified ammonia that is used in nitrogen excretion is uric acid. Uric acid is the predominant nitrogen excretory product in birds and terrestrial reptiles (turtles excrete urea, whereas alligators excrete ammonia unless they are dehydrated, in which case they, too, excrete uric acid). Uric acid formed as a product of amino acid catabolism involves the de novo pathway of purine biosynthesis therefore, its formation from NH3 liberated in amino acid catabolism is described elsewhere (see chapter 23). In mammals, uric acid is exclusively an intermediate in purine... 

Purines Are Catabolized to Uric Acid and Then to Other Products... 

Major pathways of purine degradation in animals. Primates excrete uric acid. Mammals other than primates catabolize uric acid to other end products. In contrast to the catabolism of carbohydrates, lipids, or... 

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. 

Mammals other than primates further oxidize urate by a liver enzyme, urate oxidase. The product, allantoin, is excreted. Humans and other primates, as well as birds, lack urate oxidase and hence excrete uric acid as the final product of purine catabolism. In many animals other than mammals, allantoin is metabolized further to other products that are excreted Allantoic acid (some teleost fish), urea (most fishes, amphibians, some mollusks), and ammonia (some marine invertebrates, crustaceans, etc.). This pathway of further purine breakdown is shown in figure 23.22. 

The lung also possesses nonenzymatic antioxidants such as vitamin E, beta-carotene, vitamin C, and uric acid. Vitamin E is lipid-soluble and partitions into lipid membranes, where it is positioned optimally for maximal antioxidant effectiveness. Vitamin E converts superoxide anion, hydroxyl radical, and lipid peroxyl radicals to less reactive oxygen metabolites. Beta-carotene also accumulates in cell membranes and is a metabolic precursor to vitamin A. Furthermore, it can scavenge superoxide anion and react directly with peroxyl-free radicals, thereby serving as an additional lipid-soluble antioxidant. Vitamin C is widely available in both extracellular and intracellular spaces where it can participate in redox reactions. Vitamin C can directly scavenge superoxide and hydroxyl radical. Uric acid formed by the catabolism of purines also has antioxidant properties and primarily scavenges hydroxyl radical and peroxyl radicals from lipid peroxidation. 

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... 

An increase in uric add values up to an acute gout attack can only be attributed to a minor extent to diminished uric acid excretion from the kidneys, since decreased uricosuria due to hyprerlactacid-aemia is generally not observed unless the lactate value is >2 mmol. Excessive production of uric acid caused by increased catabolism of preformed purine nucleotides is considered to be an essential cause. This is also supported by the observation that the purine nucleotide content in hver cells is diminished after prolonged alcohol consumption. (36) (s. tab. 28.2)... 

Dietary purines are largely catabolized in the gut, rather than used by the body for the synthesis of nucleic acids. The end-product of purine catabolism in humans is uric add. The diet accounts f[ir less than half of the uric add appearing in the bloodstream, Most of the plasma uric add, or urate, originates from catabolism of the purines synthesized by the body (endogenous purines). The major purines are adenine and guanine. They occur mainly as nucleotides, such as adenosine triphosphate (ATP) and guanosine triphosphate (GTP), and as parts of nucleic acids. For example, the adenine in (UvfA occurs as adenosine monophosphate, and the adenine in DNA occurs as deoxyadenosine monophosphate. 

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. 

Xanthine dehydrogenase The enz)une is used in the catabolism of the purine ring. It catalyzes the NAE>-dependent oxidation of xanthine to uric acid. The enzyme also contains FAD and molybdenum. A fraction of the enzyme normally occurs in the body as xanthine oxidase, which represents an altered form of the enzyme. Xanthine oxidase uses O2 as an oxidant, rather than NAD. Xanthine oxidase converts xanthine to uric acid, and O2 to HOOH and the hydroxyl radical. 

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... 

Uric acid is a primary end product of urine metabohsm in the kidney. Uric acid levels in human urine are like creatinine as an important parameter of renal function and a marker for renal failure as well as toxicity. As shown in Fig. 3, uric acid is the final product of catabolization of the purine nucleosides, adenosine, and guanosine. ... 

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