Uric acid precursors

Allopurinol, in contrast to the uricosuric drugs, reduces serum urate levels through a competitive inhibition of uric acid synthesis rather than by impairing renal urate reabsorption. This action is accomplished by inhibiting xanthine oxidase, the enzyme involved in the metabolism of hypoxanthine and xanthine to uric acid. After enzyme inhibition, the urinary and blood concentrations of uric acid are greatly reduced and there is a simultaneous increase in the excretion of the more soluble uric acid precursors, xanthine and hypoxanthine. 

Tubule obstruction. Given certain physicochemical conditions, crystals can deposit within the tubular lumen. Methotrexate, for example, is relatively insoluble at low pH and can precipitate in the distal nephron when the urine is acid. Similarly the uric acid produced by the metabolism of nucleic acids released during rapid tumour cell lysis can cause a fatal urate nephropathy. This was a particular problem with the introduction of chemotherapy for leukaemias until the introduction of allopurinol it is now routinely given before the start of chemotherapy to block xanthine oxidase so that the much more soluble uric acid precursor, hypoxanthine, is excreted instead. Crystal-nephropathy is also a... 

These data confirm that at this rate of ethanol administration, uric acid excretion did not decrease. The increased excretion of uric acid precursors suggests, in fact, that there is increased flux through the pathways of purine nucleotide degradation to uric acid. Excretion of labeled degradation products derived from the adenine nucleotide pool is significantly accelerated and suggests accelerated ATP or adenine nucleotide degradation. 

It has long been established that glycine incorporation into uric acid, in vivo, is enhanced in certain patients with primary or idiopathic gout (7,8). Since increased glycine incorporation into uric acid precursors can also be demonstrated in vitro in the leucocytes of patients with primary gout, a readily accessible model may be available for the study of purine metabolism in these patients, and other groups as well. 

So far no modern data existed on the response of uric acid parameters to the administration of mononucleotides, although these data are much needed to unterstand the absorption of uric acid precursors. In the following paper we will report on them. 

In a short while, it was established that the precursors of nucleic acid purines were the same as those of uric acid. N -glycine was incorporated into adenine and guanine of the nucleic acids of growing yeast 28), and the earlier observations for uric acid precursors in the pigeon were confirmed for the nucleic acids of the rat 24). It has been substantiated in a variety of tissues that formate, glycine, and CO2 all contributed in major proportions to the synthesis of allantoin 25) and nucleic acid adenine and guanine... 

Fichter and Kern O first reported that uric acid could be electrochemically oxidized. The reaction was studied at a lead oxide electrode but without control of the anode potential. Under such uncontrolled conditions these workers found that in lithium carbonate solution at 40-60 °C a yield of approximately 70% of allantoin was obtained. In sulfuric acid solution a 63% yield of urea was obtained. A complete material balance was not obtained nor were any mechanistic details developed. In 1962 Smith and Elving 2) reported that uric acid gave a voltammetric oxidation peak at a wax-impregnated spectroscopic graphite electrode. Subsequently, Struck and Elving 3> examined the products of this oxidation and reported that in 1 M HOAc complete electrochemical oxidation required about 2.2 electrons per molecule of uric acid. The products formed were 0.25 mole C02,0.25 mole of allantoin or an allantoin precursor, 0.75 mole of urea, 0.3 mole of parabanic acid and 0.30 mole of alloxan per mole of uric acid oxidized. On the basis of these products a scheme was developed whereby uric acid (I, Fig. 1) is oxidized in a primary 2e process to a shortlived dicarbonium ion (Ha, lib, Fig. 1) which, being unstable, under-... 

C. The dietary intake of purines is not a major contributing factor to uric acid blood levels. Therefore, pharmacological reduction of uric acid synthesis or increased excretion is required. Dietary restriction (A) can affect uric acid production if precursor molecules are lowered sufficiently, but this usually is not feasible. The question of drug specificity (B) is not germane to the question. Pathways of uric acid synthesis in the body (D) are well known. 

Other antioxidant species are synthesized by cells like uric acid, ubiquinol or thiols (cystein, homocystein, etc.). In addition, many compounds found in food display antioxidant properties retinol (vitamin A) and its precursor /(-carotene, and polyphenols (flavonoids, etc.). Figure 8.2 shows the apparent standard potential of some LMWA and ROS explaining the spontaneous oxido-reduction reactions at the origin of the antioxidant protection system. 

Allopurinol [al oh PURE i nole] is a purine analog. It reduces the production of uric acid by competitively inhibiting the last two steps in uric acid biosynthesis, which are catalyzed by xanthine oxidase (see Figure 39.14). [Note Uric acid is less water-soluble than its precursors. When xanthine oxidase is inhibited, the circulating purine derivatives (xanthine and hypoxanthine) are more soluble and therefore are less likely to precipitate]. 

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. 

Application of HC to animal tissues was carried out for renal stones in kidneys. Rats were freely fed a laboratory ration containing 3% uric acid and 2% potassium oxonate (54). After 3 weeks on this diet, the rats were sacrificed to obtain the kidneys. The left kidney was frozen, and the right one was fixed in absolute alcohol. Both kidneys were sectioned to observe amorphous and crystalline deposits in the tubules and collecting tubes with the microscope. Amorphous and crystalline deposits in both kidneys were removed by the microaspiratoscope, separately, for analysis by HPLC (55). To determine the constituents of the deposits, uric acid, known as a potential component of kidney stones, xanthine and hypoxanthine as precursors, and potassium oxonate were used for reference on HPLC. Only uric acid, probably urate or both, was detected in both kidneys on HPLC. 

Uric acid is associated with urea, creatine and creatinine in urine. In the urine of mammals it occurs in small amounts, the chief nitrogen compound being urea. In birds and reptiles, however, uric acid predominates and is the precursor of the related guanine in guano. 

Hyperuricaemia occurs (with precipitation of gout) due to accelerated degradation of adenine nucleotides resulting in increased production of uric acid and its precursors. Only at high alcohol concentrations does alcohol-induced high blood lactate compete for renal tubular elimination and so diminish excretion of urate. 

Just as there is no clear line of differentiation between hyperuricemic gout and normo-uricemic nongout, so there is no clear indication of the mechanism of the overproduction of uric acid. Many investigators have shown, by the administration of various labeled precursors, that in hyperuricemic and hyperuricosuric individuals there is a greater incorporation of labeled precursors into uric acid than there is in normal controls. Actually these studies merely confirm the fact that more uric acid is made by these overexcretors. If more uric acid is made, then more of the precursor must be incorporated, and we should therefore be most surprised to find that there is no increase in the labeled precursors. 

B36. Buchanan, J. M., Sonne, J. C., and Delluva, A. M., Biological precursors of uric acid. II. The role of lactate, glycine, and carbon dioxide as precursors of the carbon chain and nitrogen atom 7 of uric acid. J. Biol. Chem. 173, 81-98 (1948). B37. Bulger, H. A., and Johns, H. E., The determination of plasma uric acid. J. Biol. Chem. 140, 427-440 (1941). 

The answer is d. (Murray, pp 375-401. Scriver, pp 2513-2570. Sack, pp 121-138. Wilson, pp 287-320.) Xanthine oxidase catalyzes the last two steps in the degradation of purines. Hypoxanthine is oxidized to xanthine, and xanthine is further oxidized to uric acid. Thus, xanthine is both product and substrate in this two-step reaction. In humans, uric acid is excreted via the urine. Allopurinol, an analogue of xanthine, is used in gout to block uric acid production and deposition of uric acid crystals in the kidneys and joints. It acts as a suicide inhibitor of xanthine oxidase after it is converted to alloxanthine. Guanine can also be a precursor of xanthine. 

The answer is a. (Murray, pp 812—828. Scriver, pp 2537-2570. Sack, pp 97—158. Wilson, pp 287-320.) The child has Lesch-Nyhan syndrome (308000), an X-linked recessive disorder that is caused by HGPRT enzyme deficiency. HGPRT is responsible for the salvage ol purines from nucleotide degradation, and its deficiency elevates levels ol PRPP, purine synthesis, and uric acid. PRPP is also elevated in glycogen storage diseases due to increased amounts of carbohydrate precursors. 

Since the discovery of hydantoin in 1861, when Baeyer isolated it in his uric acid studies, that system has been an important precursor of a-amino acids owing to its lability toward alkali, especially for those acids that are difficult to prepare by other methods.300 Furthermore, the stereochemical courses of the Bucherer-Bergs and Read methods of synthesis for hydantoins (Section II,E), permit the preparation of epimeric amino acids.301-305 Some of these amino acids have been tested as possible tumor growth inhibitors,306,307 as metabolism-resistant amino acid analogues for transport system studies,72,308... 

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