Uric acid from purine 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.

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

Purine catabolism. The pathways to uric acid from guanine and adenine nucleotides are... 

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

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. 

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... 

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. 

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. 

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. 

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 (UA) is the primary end product of catabolism of purine nucleosides adenosine and guanosine and has often been regarded as a key biomarker in evaluation of physiological wellbeing [157,158], In healthy human, UA is filtered and removed from the blood by the kidneys and excreted through urine and hence kidney diseases are known to affect uric acid... 

In humans, uric acid (2,6,8-trihydroxypurine) is the major product of the catabolism of the purine nucleosides adenosine and guanosine (Figure 24-3), Purines from catabolism of dietary nucleic acid are converted to uric acid directly. The bulk of purines excreted as uric acid arise from degradation of endogenous nucleic acids. The daily synthesis rate of uric acid is approximately 400 mg dietary sources contribute... 

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... 

There were early reports that in patients with psoriasis there was a greater output of urinary uric acid (Bll) and increases in serum uric acid levels (E2). Eisen and Weissman showed that the increase in uric acid excreted was proportional to the amount of skin involved in the disease. This increase in uric acid may be partially the result of increased turnover of the diseased cells and release of their nucleic acid to the purine catabolic pool. There are other alterations in nucleic acids related to cellular metabolism in psoriasis. The ribonucleic acid concentration of psoriatic tissues is approximately 3 times that of normal skin, and the DNA can be as much as 13-14 times greater than in normal tissues (H8, W5). A fundamental change in the nature of psoriatic deoxyribonucleic acid was suggested by Steigleder et al. (S36), who isolated DNA s from psoriatic skin and from normal skin and... 

Several diseases result from defects in purine catabolic pathways. Gout, which is often characterized by high blood levels of uric acid and recurrent attacks of arthritis, is caused by several metabolic abnormalities (Special Interest Box 15.4). 

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. 

In many legumes, transportation of N from root to shoot occurs in the form of ureids, allantoin, and allantoic acid, which are synthesized from uric acid, an oxidation product of purine (xanthine). Poor growth of legumes in the presence of Mo deficiency can be ascribed in part to poor upward transport of N because of disturbed xanthine catabolism. In plants, oxidation of xanthine is mediated by another molybdoenzyme, xanthine dehydrogenase (Mendel and Muller, 1976 Nguyen and Feierabend, 1978). This enzyme has a constitution similar to that of the xanthine oxidase found in animals. It has two identical subunits, and each unit contains one Mo atom, one FAD, and four Fe-S groups. 

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. 

As is well known, the two purines, adenine and guanine, originating from nucleic acids or from high-energy phosphate compounds like ATP or GTP, are catabolized in man to uric acid. The intermediately formed hypoxanthine and xanthine are both oxidized to uric acid by the enzyme xanthine oxidase. This enzyme introduces an oxygen atom between the carbon and hydrogen atom in position Cg. Of the two tautomeric forms of uric acid, the amido (lactam) and the imido (lactim) forms, the latter has a more acid character. 

Table lO-II gives the results of one study of urinary excretion in man of allantoin and of purines other than uric acid (4 ). In addition, 1-methyl-adenine, iS -methyladenine, iVMimethylguanine, iV -methyladenosine, adenosine, and 1-methylguanosine have also been reported to be in human urine (43). The methylated purines are believed to be derived mainly from the catabolism of transfer RNA. 

XOR accelerates the hydroxylation of purines, pyrimidines, pterins and aldehydes [132]. In humans, the enzyme catalyzes the last two steps of purine catabolism the oxidation of hypoxanthine to xanthine and of the latter to uric acid. An unusual property of this, but not aU XOR enzymes [133], is its interconversion between xanthine dehydrogenase and xanthine oxidase activities which implies a switch between NAD" and molecular oxygen being used as the final electron acceptor [134]. Structural studies suggest that this switch, that can be irreversibly induced by proteolysis [135], results from conformational changes that lead to both restricted access to the NAD cofactor to its binding site and changes in the redox potential of the FAD cofactor [136],... 

In addition to their role as components of nucleoproteins, purines and pyrimidines are vital to the proper functioning of the cell. The bases are constituents of various coenzymes, such as coenzyme A (CoA), adenosine triphosphate (ATP), guanosine triphosphate (GTP), cytidine triphosphate (CTP), diphosphopyridine nucleotide (DPN), triphosphopyridine nucleotide (TPN), and flavin adenine dinucleotide (FAD). A pyrimidine derivative, cytidine diphosphate choline, is involved in phospholipid synthe another pyrimidine compound, uridine diphosphate glucose, is an important substance in carbohydrate metabolism. Cytidine diphosphate ribitol functions in the biosynthesis of a new group of bacterial cell-wall components, the teichoic acids. While mammals excrete nitrogen derived from protein catabolism in the form of urea, birds eliminate their nitrogen by synthesizing it into the purine compound, uric acid. 

If the enzyme uricase is present in the tissues, as it is in many animals, uric acid is degraded to allantoin as the end product of purine catabolism 240). Uricase was found in the liver, kidneys, and spleen of most mammals, but was absent from human tissues 268). The Dalmatian coach hound was unusual in that it excreted uric acid even though its liver contained appreciable quantities of uricase 259). It is believed that uric acid appears in the urine of this animal because of the low renal threshold for the compound 260). 

Rodents are known to possess the enzyme uricase and are therefore able to carry purine catabolism one step further than man. Preliminary results suggest that uricase is restricted to but a few rodent tissues and is absent from lines of cultured rodent cells. Hence, it may be that in each vertebrate species only the final enzyme of purine catabolism is tissue restricted it is feasible to test this generalization further. In any case, the presence of xanthine oxidase and the absence of uricase in lines of cultured rodent cells may make them useful in testing, by microbiological methods, theories about cellular factors which influence the rate of uric acid synthesis. 

---