The enzymexanthine oxidase (XO)catalyzes the formation of uric acid fromxanthine andhypoxanthine. XO, which is found in mammals, functions primarily as a dehydrogenase and rarely as an oxidase, despite its name.[8] Xanthine in turn is produced from otherpurines. Xanthine oxidase is a large enzyme whoseactive site consists of the metalmolybdenum bound tosulfur and oxygen.[9] Uric acid is released inhypoxic conditions (low oxygen saturation).[10]
In general, the watersolubility of uric acid and itsalkali metal andalkaline earthsalts is rather low. All these salts exhibit greater solubility in hot water than cold, allowing for easy recrystallization. This low solubility is significant for theetiology of gout. The solubility of the acid and its salts inethanol is very low or negligible. In ethanol/water mixtures, the solubilities are somewhere between the end values for pure ethanol and pure water.[medical citation needed]
Solubility of urate salts (grams of water per gram of compound)
Compound
Cold water
Boiling water
Uric acid
15,000
2,000
Ammonium hydrogen urate
—
1,600
Lithium hydrogen urate
370
39
Sodium hydrogen urate
1,175
124
Potassium hydrogen urate
790
75
Magnesium dihydrogen diurate
3,750
160
Calcium dihydrogen diurate
603
276
Disodium urate
77
—
Dipotassium urate
44
35
Calcium urate
1,500
1,440
Strontium urate
4,300
1,790
Barium urate
7,900
2,700
The figures given indicate what mass of water is required to dissolve a unit mass of compound indicated. The lower the number, the more soluble the substance in the said solvent.[11][12][13]
Inhumans uric acid (actually hydrogen urate ion) is the finaloxidation (breakdown) product ofpurine metabolism and is excreted in urine, whereas in most othermammals, the enzymeuricase further oxidizes uric acid toallantoin.[14] The loss of uricase in higher primates parallels the similar loss of the ability to synthesizeascorbic acid, leading to the suggestion that urate may partially substitute for ascorbate in such species.[15] Both uric acid and ascorbic acid are strongreducing agents (electron donors) and potentantioxidants. In humans, over half the antioxidant capacity ofblood plasma comes from hydrogen urate ion.[16]
The normal concentration range of uric acid (or hydrogen urate ion) in human blood is 25 to 80 mg/L for men and 15 to 60 mg/L for women[17] (but see below for slightly different values). An individual can have serum values as high as 96 mg/L and not have gout.[18] In humans, about 70% of daily uric acid disposal occurs via the kidneys, and in 5–25% of humans, impaired renal (kidney) excretion leads tohyperuricemia.[19] Normal excretion of uric acid in the urine is 270 to 360 mg per day (concentration of 270 to 360 mg/L if one litre of urine is produced per day – higher than the solubility of uric acid because it is in the form of dissolved acid urates), roughly 1% as much as the daily excretion ofurea.[20]
TheDalmatian has a genetic defect in uric acid uptake by theliver andkidneys, resulting in decreased conversion toallantoin, so this breed excretes uric acid, and not allantoin, in the urine.[21]
Inbirds andreptiles, and in some desert-dwelling mammals (such as thekangaroo rat), uric acid also is the end product of purine metabolism, but it is excreted infeces as a dry mass. This involves a complexmetabolic pathway that is energetically costly in comparison to processing of other nitrogenous wastes such asurea (from theurea cycle) orammonia, but has the advantages of reducing water loss and preventing dehydration.[22]
Platynereis dumerilii, a marinepolychaete worm, uses uric acid as a sexualpheromone. The female of the species releases uric acid into the water duringmating, which induces males to release sperm.[23]
Uric acid metabolism is done in the human gut by ~1/5 of bacteria species that come from 4 of 6 major phyla. Such metabolism is anaerobic involving uncharacterized ammonia lyase, peptidase, carbamoyl transferase, and oxidoreductase enzymes. The result is that uric acid is converted intoxanthine orlactate and theshort chain fatty acids such asacetate andbutyrate.[24] Radioisotope studies suggest about 1/3 of uric acid is removed in healthy people in their gut with this being roughly 2/3 in those with kidney disease.[25] In mouse models, such bacteria compensate for the loss of uricase leading researchers to raise the possibility "that antibiotics targeting anaerobic bacteria, which would ablate gut bacteria, increase the risk for developing gout in humans".[24]
Although foods such as meat and seafood can elevate serum urate levels, genetic variation is a much greater contributor to high serum urate.[26][27] A proportion of people have mutations in the urate transport proteins responsible for the excretion of uric acid by the kidneys. Variants of a number of genes, linked to serum urate, have so far been identified:SLC2A9;ABCG2;SLC17A1;SLC22A11;SLC22A12;SLC16A9;GCKR;LRRC16A; andPDZK1.[28][29][30] GLUT9, encoded by theSLC2A9 gene, is known to transport both uric acid andfructose.[19][31][32]
Myogenichyperuricemia, as a result of thepurine nucleotide cycle running when ATP reservoirs in muscle cells are low, is a common pathophysiologic feature ofglycogenoses, such asGSD-III, which is ametabolic myopathy impairing the ability of ATP (energy) production for muscle cells.[33] In these metabolic myopathies, myogenic hyperuricemia is exercise-induced; inosine, hypoxanthine and uric acid increase in plasma after exercise and decrease over hours with rest.[33] Excess AMP (adenosine monophosphate) is converted into uric acid.[33]
In humanblood plasma, thereference range of uric acid is typically 3.4–7.2 mg per 100 mL(200–430 μmol/L) for men, and 2.4–6.1 mg per 100 mL for women (140–360 μmol/L).[34] Uric acid concentrations in blood plasma above and below the normal range are known as, respectively,hyperuricemia andhypouricemia. Likewise, uric acid concentrations in urine above and below normal are known ashyperuricosuria and hypouricosuria. Uric acid levels in saliva may be associated with blood uric acid levels.[35]
A 2011 survey in the United States indicated that 3.9% of the population had gout, whereas 21.4% had hyperuricemia without having symptoms.[43]
Excess blood uric acid (serum urate) can inducegout,[44] a painful condition resulting from needle-like crystals of uric acid termedmonosodium urate crystals[45] precipitating injoints,capillaries,skin, and other tissues.[46] Gout can occur where serum uric acid levels are as low as 6 mg per 100 mL (357 μmol/L), but an individual can have serum values as high as 9.6 mg per 100 mL (565 μmol/L) and not have gout.[18]
In humans, purines are metabolized into uric acid, which is then excreted in the urine. Consumption of large amounts of some types of purine-rich foods, particularly meat and seafood, increases gout risk.[47] Purine-rich foods include liver, kidney, andsweetbreads, and certain types of seafood, including anchovies, herring, sardines, mussels, scallops, trout, haddock, mackerel, and tuna.[48] Moderate intake of purine-rich vegetables, however, is not associated with an increased risk of gout.[47]
One treatment for gout in the 19th century was administration oflithium salts;[49] lithium urate is more soluble. Today, inflammation during attacks is more commonly treated withNSAIDs,colchicine, orcorticosteroids, and urate levels are managed withallopurinol.[50] Allopurinol, which weakly inhibits xanthine oxidase, is an analog of hypoxanthine that is hydroxylated byxanthine oxidoreductase at the 2-position to give oxipurinol.[51]
Tumor lysis syndrome, an emergency condition that may result fromblood cancers, produces high uric acid levels in blood when tumor cells release their contents into the blood, either spontaneously or followingchemotherapy.[41] Tumor lysis syndrome may lead toacute kidney injury when uric acid crystals are deposited in the kidneys.[41] Treatment includes hyperhydration to dilute and excrete uric acid viaurine,rasburicase to reduce levels of poorly soluble uric acid in blood, or allopurinol to inhibitpurinecatabolism from adding to uric acid levels.[41]
Lesch–Nyhan syndrome, a rare inherited disorder, is also associated with high serum uric acid levels.[52] Spasticity, involuntary movement, and cognitive retardation as well as manifestations of gout are seen in this syndrome.[53]
Hyperuricemia is associated with an increase inrisk factors forcardiovascular disease.[54] It is also possible that high levels of uric acid may have a causal role in the development of atherosclerotic cardiovascular disease, but this is controversial and the data are conflicting.[55]
Comparison of different types of urinary crystals.
Kidney stones can form through deposits of sodium urate microcrystals.[56]
Saturation levels of uric acid in blood may result in one form ofkidney stones when the urate crystallizes in the kidney. These uric acid stones areradiolucent, so do not appear on an abdominal plainX-ray.[57] Uric acid crystals can also promote the formation ofcalcium oxalate stones, acting as "seed crystals".[58]
Low uric acid (hypouricemia) can have numerous causes. Low dietaryzinc intakes cause lower uric acid levels. This effect can be even more pronounced in women taking oral contraceptive medication.[61]Sevelamer, a drug indicated for prevention ofhyperphosphataemia in people withchronic kidney failure, can significantly reduce serum uric acid.[62]
Meta-analysis of 10 case-control studies found that the serum uric acid levels of patients withmultiple sclerosis were significantly lower compared to those of healthy controls, possibly indicating a diagnosticbiomarker for multiple sclerosis.[63]
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