Uric acid biosynthesis

It inhibits the terminal steps in uric acid biosynthesis by inhibiting enzyme xanthine oxidase. During therapy with allopu-rinol the uric acid plasma levels decline. 

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 treatment of the chronic gouty patient aims at maintaining the lowest possible blood uric acid level. This can be achieved either by preventing reabsorption of uric acid in the proximal tubules or by blocking uric acid biosynthesis through normal metabolic pathways. 

Brandenberger, H. 1954. The oxidation of uric acid to oxonic acid (allantoxanic acid) and its application in tracer studies of uric acid biosynthesis. Biochim. Biophys. Acta. 15 108. 

The important effect on the oxypurine excretion (with high ratio of hypoxanthine/xanthine)during allopurinol therapy and the inefficacy of thiopurinol, in both patients LUG., and MON., (m) are quite the same as in patient with complete deficiency. They have 50 % of control values of rate of synthesis of alio and thiopurinol nucleotide in vitro. (PRPP content of erythrocytes is normal.) The response of allopurinol therapy on uric acid and oxypurine excretion in the mother of LESCH-NYHAN BRE., (m) is the same as other gouty patient with normal HGPRT and normal rate of synthesis of alio and thiopurinol nucleotide. The gouty patient GIR., with partial deficiency of APRT (38 of normal) has an important overproduction of uric acid. This was confirmed by incorporation of labeled glycine into uric acid (DELBARRE et al 1969). Allopurinol and thiopurinol has an explosive effect on uric acid biosynthesis de novo (-U0 ). With allopurinol therapy there... 

Lipoxygenases (LOX), cycloxygenases (COXs), and xanthine oxidase (XO) are metalloen-zymes whose catalytic cycle involves ROS such as lipid peroxyl radicals, superoxide, and hydrogen peroxide. LOXs and COXs catalyze important steps in the biosynthesis of leuco-trienes and prostaglandins from arachidonic acid, which is an important cascade in the development of inflammatory responses. XO catalyzes the ultimate step in purine biosynthesis, the conversion of xanthine into uric acid. XO inhibition is an important issue in the... 

Several purine derivatives are found in nature, e.g. xanthine, hypoxanthine and uric acid. The pharmacologically important (CNS-stimulant) xanthine alkaloids, e.g. caffeine, theobromine and theophylline, are found in tea leaves, coffee beans and coco. The actual biosynthesis of purines involves construction of a pyrimidine ring onto a pre-formed imidazole system. 

Gout is caused by the deposition of crystals of monosodium urate hydrate which are ingested by leucocyctes and trigger the inflammatory response. The biosynthesis of uric acid involves the oxidation of the more soluble compound xanthine (2,6-dihydroxypurine) by xanthine oxidase, and this enzyme is inhibited by allopurinol (187). The treatment of gout also relies on uricosuric drugs to accelerate urinary excretion of uric acid and antiinflammatory drugs to ease the pain and inflammation. 

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... 

Chronic gout can be caused by (1) a genetic defect, for example, one resulting in an increase in the rate of purine synthesis, (2) renal deficiency, (3) Lesch-Nyhan Syndrome,4 or (4) excessive synthesis of uric acid associated with cancer chemotherapy. Treatment strategies for chronic gout include the use of uricosuric drugs that increase the excretion of uric acid, thereby reducing its concentration in plasma, and the use of allopurinol, which is a selective inhibitor of the terminal steps in the biosynthesis of uric acid. 

The hyperuricemia in Lesch-Nyhan patients is explained, at least in part, on the basis of intracellular accumulation of PRPP leading to increased purine nucleotide biosynthesis de novo and increased production of uric acid. Such patients do not usually develop gouty arthritis early in life but do exhibit uric acid crystalluria and stone formation. 

Examination of the urine of subjects receiving EATDA showed that several, if not all, of the urinary purines were excreted in increased amounts. There was, furthermore, no change in the mode of excretion of urates or in the proportion disposed of extrarenally (S12). The suggestion has been made (K18) that the fundamental mechanism of action of these compounds is the blocking of the incorporation of newly synthesized adenine into polynucleotides and/or coenzymes, with the production of an undefined deficiency state. This block could stimulate a compensatory increase in purine biosynthesis. The excess purines would not be utilizable and, therefore, would be excreted from the cells, and the normal degradation by enzymes would convert this material to uric acid. 

See also De Novo Biosynthesis of Purine Nucleotides, Purine Degradation, Excessive Uric Acid in Purine Degradation, Salvage Routes to Deoxyribonucleotide Synthesis, Nucleotide Analogs in Selection... 

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