Gout, purine metabolism

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

Curto R> Voit EO, Cascante M Analysis of abnormalities in purine metabolism leading to gout and to neurological dysfunctions in man. Biochem J 1998 3 29 477. 

Gout A group of disorders of purine metabolism, manifested by various combinations of hyperuricemia recurrent acute inflammatory arthritis induced by crystals of monosodium urate monohydrate tophaceous deposits of monosodium urate monohydrate crystals in and around the joints of the extremities, which may lead to crippling destruction of joints and uric acid urolithiasis. 

Uric acid A by-product of purine metabolism in mammals, including humans. A high serum uric acid concentration is a major risk factor for gout. 

Uric acid is the end product of the purine metabolism. When uric acid excretion via the kidneys is disturbed, gout can develop (see p. 190). Creatinine is derived from the muscle metabolism, where it arises spontaneously and irreversibly by cyclization of creatine and creatine phosphate (see p. 336). Since the amount of creatinine an individual excretes per day is constant (it is directly proportional to muscle mass), creatinine as an endogenous substance can be used to measure the glomerular filtration rate. The amount of amino acids excreted in free form is strongly dependent on the diet and on the ef ciency of liver function. Amino acid derivatives are also found in the urine (e.g., hippu-rate, a detoxification product of benzoic acid). 

Gout is a metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage. Uric acid renal calculi, tophi, and interstitial nephritis may also occur. Gout is usually associated with hyperuricemia, high serum levels of uric acid, a poorly soluble substance that is the major end product of purine metabolism. In most mammals, uricase converts uric acid to the more soluble allantoin this enzyme is absent in humans. While clinical gouty episodes are associated with hyperuricemia, most individuals with hyperuricemia may never develop a clinical event from urate crystal deposition. 

A condition known as Lesch-Nyhan syndrome is one of the primary causes of gout. An X-linked recessive trait occurring in males, this condition involves a tremendous overproduction of uric acid due to a deficiency of one of the enzymes involved in purine metabolism, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Other abnormalites lead to mental retardation and aggressive behavior. An obvious symptom of the condition is self-mutilation. 

Gout is a relatively common ( 3 per 1,000 persons) derangement of purine metabolism that is associated with elevated plasma levels of uric acid. The excessive uric acid leads to painful deposits of monosodium urate in the... 

Uric acid is one of the principal end products of purine metabolism. Gout is caused by elevated levels of uric acid in the body, causing crystals of urate salts to precipitate in the joints. 

Xanthine oxidases occur in the liver and kidneys of humans and animals, and cow s milk is a good source of the enzyme (16, 17, 37). These enzymes catalyze the final step in purine metabolism in primates, the production of uric acid. An excess of uric acid crystallizes in joints producing inflammation (i.e., gout) this condition can be relieved by treatment with allopurinol, an inhibitor of xanthine oxidase. 

Kelley WN. Gout and related disorders of purine metabolism. In Textbook of Rheumatology (P edition). Kelly WN, Harris Jr ED, Sledge CB, editors. WB Saunders, Philadelphia 1981 p. 1397-1437. 

Uric acid is the chief end product of purine metabolism in primates, birds, lizards, and snakes. An inborn metabolic error in humans results in increased levels of uric acid and its deposition as painful crystals in the joints. This condition (gout) may be treated by the drug allopurinol which is also oxidized by xanthine oxidase to allo-xanthine (dashed line in Eq. 19.29). However, alloxanthine binds so tightly to the molybdenum that the enzyme is inactivated, the catalytic cycle broken, and uric acid formation is inhibited. The extra stability of the alloxanthine complex may be a result of strong N—H --N hydrogen bonding by the nitrogen in the 8-position ... 

Several disorders affect purine metabolism. They are gout and the syndromes associated with deficiency of HPRT, APRT, adenosine deaminase, nucleoside phosphorylase, myoadenylate deaminase, and xanthine oxidase. 

Primary gout is a disorder of purine metabolism seen predominantly in men. The condition is multifactorial and involves genetic and nongenetic factors. Occurrence in women is uncommon when it does occur, it is usually found in postmenopausal women. The blood urate concentration of normal men is 1 mg/dL higher than that in women, but this difference disappears after the menopause. Thus, in women, the postmenopausal rise in serum urate levels may increase the risk of developing gout. Gout is very rare in children and adolescents. 

B21. Blumberg, B. S., Heredity of gout and hyperuricemia in gout and purine metabolism. Arthritis Rheumd. 8, 627-633 (1965). 

Figure 22.9 shows that gout can be caused by abnormalities in three different enzymes in purine metabolism. 

The pathophysiology of gout is understood poorly. While a prerequisite, hyperuricemia does not inevitably lead to gout. Uric acid, the end product of purine metabolism, is relatively insoluble compared to its hypoxanthine and xanthine precursors, and normal serum urate levels approach the limit of solubility. In most patients with gout, hyperuricemia arises from underexcretion rather than overproduction of urate. Urate tends to crystallize in colder or more acidic conditions. Neutrophils ingesting urate crystals secrete inflammatory mediators that lower the local pH and lead to further urate precipitation. 

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