Purines catabolism

Oxypurines are end products of purine metabolism in man. They do not serve as a general end product of nitrogen, as is the case with some 

Many other ribonucleases have been described. They differ with respect to specificity toward various internucleotide bonds, in heat stabilities, and in pH optima. In 1949 Maver and Greco (M8) reported the presence in extracts of spleen of a heat-labile nuclease that had a pH optimum of approximately 5.2 in the presence of magnesium, and 6.6 in the absence of magnesium. That this was a different enzyme entirely from pancreatic RNase was shown most dramatically by Hilmoe and Heppel (H7), who found that this enzyme was able to hydrolyze the limit polynucleotide obtained by exhaustive treatment of RNA with ribonuclease I. The ubiquity of ribonucleases can perhaps best be demonstrated by noting 

There may be many proteins that inhibit ribonucleases. Clear evidence has been presented that there is at least one such substance in rat liver that is a powerful and specific inhibitor of the pancreatic enzyme, but is inactive against RNases obtained from plants or bacteriophage (R14, S17). 

Variations in RNase levels may occur in several diseases (Section 5.2). These changes may be of a fundamental nature for example, Daoust and Amano (D3) have postulated that the loss of ribonucleases is a common characteristic of tumors in general. In view of the several RNA s that are known and the several RNases that have been described, a variety of relationships are possible. Without more information it is impossible to evaluate this hypothesis. 

Another enzyme of possible significance in this metabolic area is polynucleotide phosphorylase, which was first viewed as primarily a catalyst for RNA s3mthesis. The reaction involved is the reversible polymerization of ribonucleotide 6 -diphosphates with the concomitant liberation of inorganic phosphate (G17). It is quite possible that the biological role of this enzyme is the reverse reaction, i.e., the production of nucleoside diphosphates from RNA. 

Two different enzymes with different specificities with respect to the purine 

Purines are degraded to uric acid in primates (including humans) and further degraded in other organisms. Overproduction of uric acid causes gout in humans. 

Salvage reactions exist for reuse of some of purines. 

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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. 

While purine deficiency states are rare in human subjects, there are numerous genetic disorders of purine catabolism. Hyperuricemias may be differentiated based on whether patients excrete normal or excessive quantities of total urates. Some hyperuricemias reflect specific en2yme defects. Others are secondary to diseases such as cancer or psoriasis that enhance tissue turnover. 

Unlike the end products of purine catabolism, those of pyrimidine catabolism are highly water-soluble COj, NH3, P-alanine, and P-aminoisobutyrate (Figure 34-9). Excretion of P-aminoisobutyrate increases in leukemia and severe x-ray radiation exposure due to increased destruction of DNA. However, many persons of Chinese or Japanese ancestry routinely excrete P-aminoisobutyrate. Humans probably transaminate P-aminoisobutyrate to methylmalonate semialdehyde, which then forms succinyl-CoA (Figure 19-2). 

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. 

Schultz AC, P Nygaard, HH Saxild (2001) Functional analysis of 14 genes that constitute the purine catabolic pathway in Bacillus subtilis and evidence for a novel regulon controlled by the PucR transcription activator. J Bacteriol 183 3293-3302. 

Xi H, BL Schneider, L Reitzer (2000) Purine catabolism in Escherichia coli and function of xanthine dehydrogenase in purine salvage J Bacterial 182 5332-5341. 

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). 

Uricase Purine catabolism Pigs, soybeans Pitts et al. (1974)... 

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. 

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. 

Peroxisomes are small granules arranged in clusters around the smooth ER and glycogen stores. They contain about 50 enzymes, some of which are used in respiration, purine catabolism and alcohol metabolism. They are responsible for about 20% of the oxygen consumption in the liver via a respiratory pathway that produces heat rather than ATP as its product. They differ from lysosomes in that they are not formed from outgrowths of the Golgi apparatus but are self-replicating, rather like mitochondria. They also play an important role in the metabolism of fatty acids as well as cholesterol and bile acid synthesis. 

The enzymes are widely distributed in microorganisms, plants, and animals. " Three Mo-MPT enzymes have been found in mammals (1) xanthine dehydrogenase see Dehydrogenase) has many, varied roles in purine catabolism, drug metabolism, and oxidative stress response, (2) aldehyde oxidase is important in drug metabolism and the synthesis of retinoic acid from retinal, and (3) sulfite oxidase plays a cmcial role in the detoxification of sulfite produced in the degradation of cysteine and methionine. Genetic Mo-MPT deficiency in... 

Figure 25.17. Purine Catabolism. Purine bases are converted first into xanthine and then into urate for excretion. Xanthine oxidase catalyzes two steps in this process.

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. 

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) ... 

Reactions catalyzed by adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP). ADA and PNP participate in the purine catabolic pathway, and deficiency of either leads to immunodeficiency disease. [Slightly modified and reproduced, with permission, from N. M. Kredich and M. S. Hershfield, Immunodeficiency diseases caused by adenosine deaminase and purine nucleoside phosphorylase deficiency. In The Metabolic Basis of Inherited Disease, 6th ed., C. S. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, Eds. New York McGraw-Hill (1989).]... 

Pyrimidine catabolism occurs mainly in the liver. In contrast to purine catabolism, pyrimidine catabolism yields highly soluble end products. Pyrimidine nucleotides are converted to nucleosides by 5 -nucleotidase. 

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... 

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