Purines urate oxidase

Purine metabolism in some mammals is characterized by a further oxidation of uric acid to al-lantoin by the enzyme urate oxidase. Allantoin is significantly more water soluble than uric acid and is also freely excreted via the renal route. 

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. 

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. 

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. 

P. are particularly abundant in liver and kidney cells, e.g. a single rat liver cell contains 350-400 P. The half-life of P. is 1.5-2 days. Other cell types usually contain smaller P. with homogeneous contents (microperoxisomes). In addition to catalase, P. contain, inter alia, o-amino acid oxidase, a-hydroxyacid oxidase and urate oxidase. The latter enzyme is often present as a large crystal in the otherwise homogeneous matrix. These enzymes are particularly important in the oxidative degradation of metabolic intermediates (e.g. purine bases) and in the formation of carbohydrates from amino acids and other materials. [L.J. Olsen J.J.Harada Peroxisomes and Their Assembly in Higher Plants Annu. Rev. Plant Physiol. Plant Mol. BioL 46 (1995) 123-146)... 

Fig. 181. Degradation of the purine ring system via allantoin to glyoxylic acid and urea 1 Xanthine oxidase or xanthine dehydrogenase 2 urate oxidase 3 allantoinase 4 allantoicase...

The main end product of purine—adenine, guanine and xanthine—metabolism in birds, reptiles, and man, which is excreted in the urine. Uric acid is formed from purines consumed in the diet, and from body purines derived from the breakdown of nucleic acids. Mammals other than man further metabolize uric acid to allantoin, which is excreted in the urine. However, man lacks the enzyme, urate oxidase, necessary for this conversion. Therefore, about 0.5 to 1.0 g of uric acid is lost in the urine each day. A high level of uric acid in the blood is associated with the development of gout. In addition, uric acid may form kidney stones, especially in individuals suffering from gout. 

Peroxisomes are more recently recognized intracellular structures that contain catalase, D-amino acid oxidase, and urate oxidase (Masters and Holmes, 1977). The cytoplasm contains some or all of the enzymes of the glycolytic, pentose phosphate, galactose, uronic acid, glycogen, fructose, mucopolysaccharide, pyrimidine, purine, amino acid, fatty acid biosynthetic, and other metabolic pathways. 

Febuxostat is a potent and selective inhibitor of xanthine oxidase, and thereby reduces the formation of xanthine and uric acid. No other enzymes involved in purine or pyrimidine metabolism are inhibited. In clinical trials, febuxostat at a daily dose of 80 mg or 120 mg was more effective than allopurinol at a standard 300 mg daily dose in lowering serum urate levels. The urate-lowering effect was comparable regardless of the pathogenic cause of hyperuricemia—overproduction or underexcretion. 

If properly controlled, simple gout may have few adverse effects. However, the severe neurological symptoms of Lesch-Nyhan syndrome (Section E,2 of text)6 cannot be corrected by medication. Colchicine (Box 7-D), in a manner which is not understood, alleviates the painful symptoms of gout caused by the deposits of sodium urate in joints and tissues. It is also important to keep the dietary purine intake low and it is often necessary to inhibit xanthine oxidase. A widely used and effective inhibitor is the isomer of hypoxanthine known as allopurinol, which is taken daily in amounts of 100 -600 mg or more. 

The decrease in rate of reaction of xanthine oxidase with the size of purine substrate is also consistent with a size-selective active site pocket and possible metal binding of substrate [242,243], A strongly coupled nitrogen is not observed in the very rapid signal, which is thought to include bound product, so it would appear that the urate is not N bound to the molybdenum center [152-158],... 

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.

Gout is a group of diseases caused by an increased conversion of purine bases to uric acid or a decreased excretion of uric acid by the kidney. Thus uric acid, which is very insoluble, accumulates, resulting in the precipitation of urate crystals in the joints, which causes acute inflammatory arthritis. Chronic cases are treated with allopurinol, a base that forms a nucleotide that inhibits xanthine oxidase and prevents hypoxanthine and xanthine from being converted to uric acid (see Figure 7-22A). 

In a commercially available assay, serum NTP catalyzes the hydrolysis of IMP to yield inosine, which is then converted to hypoxanthine by purine-nucleoside phosphorylase (EC 2.4.2.1). Hypoxanthine is oxidized to urate with xanthine oxidase (EC 1.2.3.2). Two moles of hydrogen peroxide are produced for each mole of hypoxanthine liberated and converted to uric acid. The formation rate of hydrogen peroxide is monitored by a spectrophotometer at 510nm by the oxidation of a chromogenic system. The effect of ALPs on IMP is inhibited by p-glycerophosphate. This material is substrate for ALP but not for NTP, and by forming substrate complexes with the former enzyme, it reduces the proportion of the total ALP activity that is directed to the hydrolysis of the NTP substrate, IMP. ... 

A wide variety of compounds have been shown to inhibit xanthine oxidase guanidines and some triazines (F7), purine derivatives such as purine 6-aldehyde (G5), 6-mercaptopurine (S20), 2,6-diaminopurine (W8), flavonoids (B13), and Antabuse (R6). Although these compounds and the inhibitions they produce are of interest in understanding the nature of the action of xanthine oxidase, none has been useful clinically in limiting urate production. Antabuse, as a result of its action, produces other effects that (fortunately ) have not been found with allopurinol. 

Uric acid (Fig. 1) in the human body is the end product of purine metabolism. It is produced by the enzymatic conversion of hypoxanthine to xanthine and then to uric acid. The enzyme involved here is xanthine oxidoreductase. This enzyme exists in two forms xanthine dehydrogenase and xanthine oxidase. The latter is able to produce oxidizing species during enzymatic catalysis [4]. In most organisms uric acid is enzymatically degraded by an enzyme called urate... 

Xanthine oxidase The enzyme that catalyzes the final steps in purine degradation to produce urate. This enzyme is inhibited by compounds such as aUopurinol in treatment regimens designed to decrease sodium urate concentrations in the blood. 

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