| Uric acid | |
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7,9-Dihydro-1H-purine-2,6,8(3H)-trione |
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Other names
2,6,8-Trioxypurine |
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| Identifiers | |
| CAS number | 69-93-2 |
| PubChem | 1175 |
| ChemSpider | 1142 |
| UNII | 268B43MJ25 |
| EC number | 200-720-7 |
| DrugBank | DB01696 |
| KEGG | C00366 |
| MeSH | Uric+Acid |
| ChEBI | CHEBI:27226 |
| ChEMBL | CHEMBL792 |
| Beilstein Reference | 156158 |
| 3DMet | B00094 |
| Jmol-3D images | Image 1 Image 2 |
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| Properties | |
| Molecular formula | C5H4N4O3 |
| Molar mass | 168.1103 g mol-1 |
| Exact mass | 168.028340014 g mol-1 |
| Appearance | White crystals |
| Melting point |
300 °C, 573 K, 572 °F |
| Solubility in water | 60 mg dm-3 (at 20 °C) |
| log P | -1.107 |
| Acidity (pKa) | 5.6 |
| Basicity (pKb) | 8.4 |
| Thermochemistry | |
| Std enthalpy of formation ΔfH |
-619.69--617.93 kJ mol-1 |
| Std enthalpy of combustion ΔcH |
-1.9212--1.91956 MJ mol-1 |
| Standard molar entropy S |
173.2 J K-1 mol-1 |
| Specific heat capacity, C | 166.15 J K-1 mol-1 (at 24.0 °C) |
| (verify) (what is: /?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) |
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| Infobox references | |
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid can lead to a type of arthritis known as gout. The chemical is associated with other medical conditions like ammonium acid urate kidney stones.
Contents |
Uric acid is a diprotic acid with pKa1=5.4 and pKa2=10.3.[1] Thus in strong alkali at high pH, it forms the dually charged full urate ion, but at biological pH or in the presence of carbonic acid or carbonate ions, it forms the singly charged hydrogen or acid urate ion as its pKa2 is greater than the pKa1 of carbonic acid. As its second ionization is so weak, the full urate salts tend to hydrolyze back to hydrogen urate salts and free base at pH values around neutral. It is aromatic because of the purine functional group.
As a bicyclic, heterocyclic purine derivative, uric acid does not protonate like carboxylic acids. X-Ray diffraction studies on the hydrogen urate ion in crystals of ammomium hydrogen urate, formed in vivo as gouty deposits, reveal the keto-oxygen in the 2 position of a tautomer of the purine structure exists as a hydroxyl group and the two flanking nitrogen atoms at the 1 and 3 positions share the ionic charge in the six membered pi-resonance-stabilized ring.[2]
Thus, whereas most organic acids are deprotonated by the ionization of a polar hydrogen-to-oxygen bond, usually accompanied by some form of resonance stabilization (resulting in a carboxylate ion), uric acid is deprotonated at a nitrogen atom and uses a tautomeric keto/hydroxy group as an electron-withdrawing group to increase the pK1 value. The five membered ring also possesses a keto group (in the 8 position), flanked by two secondary amino groups (in the 7 and 9 positions), and deprotonation of one of these at high pH could explain the pK2 and behavior as a diprotic acid. Similar tautomeric rearrangement and pi-resonance stabilization would then give the ion some degree of stability. (On the structure shown at the upper right, the NH at the upper right on the six membered ring is "1", counting clockwise around the six membered ring to "6" for the keto carbon at the top of the six membered ring. The upper most NH on the five membered ring is "7", counting counter clockwise around this ring to the lower NH, which is "9".)
Uric acid was first isolated from kidney stones in 1776 by Scheele.[3] As far as laboratory synthesis is concerned, in 1882, Horbaczewski claimed to have prepared uric acid by melting urea hydrogen peroxide with glycine, trichlorolactic acid, and its amide. Soon after, repetition by Eduard Hoffmann shows that this preparation with glycine gives no trace of uric acid, but trichlorolactimide produces some uric acid. Thus, Hoffmann was the first to synthesize uric acid.[4]
Generally, the water solubilitity of uric acid and its alkali metal and alkaline earth salts is rather low. All these salts exhibit greater solubility in hot water than cold, allowing for easy recrystallization. This low solubility is significant for the etiology of gout. The solubility of the acid and its salts in ethanol is very low or negligible. In ethanol water mixtures, the solubilities are somewhere between the end values for pure ethanol and pure water.
| Compound | Cold Water | Boiling Water |
|---|---|---|
| Uric Acid | 15000 | 2000 |
| NH4HUrate | - | 1600 |
| LiHUrate | 370 | 39 |
| NaHUrate | 1175 | 124 |
| KHUrate | 790 | 75 |
| Mg(HUrate)2 | 3750 | 160 |
| Ca(HUrate)2 | 603 | 276 |
| Na2Urate | 77 | - |
| K2Urate | 44 | 35 |
| CaUrate | 1500 | 1440 |
| SrUrate | 4300 | 1790 |
| BaUrate | 7900 | 2700 |
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.[5][6][7]
The enzyme xanthine oxidase makes uric acid from xanthine and hypoxanthine, which in turn are produced from purines. Xanthine oxidase is a large enzyme whose active site consists of the metal, molybdenum, binded to sulfur and oxygen.[8] Within cells, xanthine oxidase can exist as xanthine dehydrogenase and xanthine oxireductase, which has also been purified from bovine milk and spleen extracts.[9] Uric acid is released in hypoxic conditions.[10]
In humans and higher primates, uric acid is the final oxidation (breakdown) product of purine metabolism and is excreted in urine. In most other mammals, the enzyme uricase further oxidizes uric acid to allantoin.[11] The loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid, leading to the suggestion that urate may partially substitute for ascorbate in such species.[12] Both uric acid and ascorbic acid are strong reducing agents (electron donors) and potent antioxidants. In humans, over half the antioxidant capacity of blood plasma comes from uric acid.[13] The Dalmatian dog has a genetic defect in uric acid uptake by the liver and kidneys, resulting in decreased conversion to allantoin, so this breed excretes uric acid, and not allantoin, in the urine.[14]
In birds and reptiles, and in some desert dwelling mammals (e.g., the kangaroo rat), uric acid also is the end product of purine metabolism, but it is excreted in feces as a dry mass. This involves a complex metabolic pathway that is energetically costly in comparison to processing of other nitrogenous wastes such as urea (from urea cycle) or ammonia, but has the advantage of reducing water loss.[15]
In humans, about 70% of daily uric acid disposal occurs via the kidneys, and in 5-25% of humans, impaired renal (kidney) excretion leads to hyperuricemia.[16]
A proportion of people have mutations in the proteins responsible for the excretion of uric acid by the kidneys. Nine genes have so far been identified: SLC2A9; ABCG2; SLC17A1; SLC22A11; SLC22A12; SLC16A9; GCKR; LRRC16A; and PDZK1.[17][18] SLC2A9 is known to transport both uric acid and fructose.[16][19]
In human blood plasma, the reference range of uric acid is between 3.6 mg/dL (~214 µmol/L) and 8.3 mg/dL (~494 µmol/L) (1 mg/dL=59.48 µmol/L).[20] This range is considered normal by the American Medical Association Manual of Style.[21] Uric acid concentrations in blood plasma above and below the normal range are known, respectively, as hyperuricemia and hypouricemia. Similarly, uric acid concentrations in urine above and below normal are known as hyperuricosuria and hypouricosuria. Such abnormal concentrations of uric acid are not medical conditions, but are associated with a variety of medical conditions.
High levels of uric acid is called hyperuricemia.
Excess serum accumulation of uric acid can lead to a type of arthritis known as gout.[24] This painful condition is the result of needle-like crystals of uric acid precipitating in joints and capillaries. Kidney stones can also form through the formation and deposition of sodium urate microcrystals.[25]
It has also been found that men who drank two or more sugar-sweetened beverages a day have an 85% higher chance of developing gout than those who drank such beverages infrequently.[26]
Gout can occur where serum uric acid levels are as low as 6 mg/dL (~357 µmol/L), but an individual can have serum values as high as 9.6 mg/dL (~565 µmol/L) and not have gout.[27]
One treatment for gout, in the 19th century, had been administration of lithium salts;[28] lithium urate is more soluble. Today, inflammation during attacks is more commonly treated with NSAIDs, and urate levels are managed with allopurinol.[29] Allopurinol, developed over 30 years ago by Elion et al., weakly inhibits xanthine oxidase. It is an analog of hypoxanthine that is hydroxylated by xanthine oxireductase at the 2-position to give oxipurinol. Oxipurinol has been supposed to bind tightly to the reduced molybdenum ion in the enzyme and thus inhibits uric acid synthesis.[30]
Lesch-Nyhan syndrome, an extremely rare inherited disorder, is also associated with very high serum uric acid levels.[31] Spasticity, involuntary movement and cognitive retardation as well as manifestations of gout are seen in cases of this syndrome.[32]
Although uric acid can act as an antioxidant, excess serum accumulation is often associated with cardiovascular disease. It is not known whether this is causative (e.g., by acting as a prooxidant ) or a protective reaction taking advantage of urate's antioxidant properties.[24][33] The same may account for the putative role of uric acid in the etiology of stroke.[34]
The association of high serum uric acid with insulin resistance has been known since the early part of the 20th century, nevertheless, recognition of high serum uric acid as a risk factor for diabetes has been a matter of debate. In fact, hyperuricemia has always been presumed to be a consequence of insulin resistance rather than its precursor.[35] However, a prospective follow-up study showed high serum uric acid is associated with higher risk of type 2 diabetes, independent of obesity, dyslipidemia, and hypertension.[36]
Hyperuricemia is associated with components of metabolic syndrome. A study has suggested fructose-induced hyperuricemia may play a pathogenic role in the metabolic syndrome.[37] This is consistent with the increased consumption in recent decades of fructose-containing beverages (such as fruit juices and soft drinks sweetened with sugar and high-fructose corn syrup) and the epidemic of diabetes and obesity.[26]
Saturation levels of uric acid in blood may result in one form of kidney stones when the urate crystallizes in the kidney. These uric acid stones are radiolucent and so do not appear on an abdominal plain X-ray. Their presence must be diagnosed by ultrasound for this reason. Very large stones may be detected on X-ray by their displacement of the surrounding kidney tissues.
Uric acid stones, which form in the absence of secondary causes such as chronic diarrhea, vigorous exercise, dehydration, and animal protein loading, are felt to be secondary to obesity and insulin resistance seen in metabolic syndrome. Increased dietary acid leads to increased endogenous acid production in the liver and muscles, which in turn leads to an increased acid load to the kidneys. This load is handled more poorly because of renal fat infiltration and insulin resistance, which are felt to impair ammonia excretion (a buffer). The urine is therefore quite acidic, and uric acid becomes insoluble, crystallizes and stones form. In addition, naturally present promoter and inhibitor factors may be affected. This explains the high prevalence of uric stones and unusually acidic urine seen in patients with type 2 diabetes. Uric acid crystals can also promote the formation of calcium oxalate stones, acting as "seed crystals" (heterogeneous nucleation).[38]
Low uric acid (hypouricemia) can have numerous causes.
Low dietary zinc intakes cause lower uric acid levels. This effect can be even more pronounced in women taking oral contraceptive medication.[39]
Xanthine oxidase is an Fe-Mo enzyme, so people with Fe deficiency (the most common cause of anemia in young women) or Mo deficiency can experience hypouricemia.
Xanthine oxidase loses its function and gains ascorbase function when some of the Fe atoms in XO are replaced with Cu atoms. Accordingly, people with high Cu/Fe can experience hypouricemia and vitamin C deficiency, resulting in oxidative damage. Since estrogen increases the half life of Cu, women with very high estrogen levels and intense blood loss during menstruation are likely to have a high Cu/Fe and present with hypouricemia.
Sevelamer, a drug indicated for prevention of hyperphosphataemia in patients with chronic renal failure, can significantly reduce serum uric acid.[40]
Lower serum values of uric acid have been associated with multiple sclerosis (MS). MS patients have been found to have serum levels ~194 µmol/L, with patients in relapse averaging ~160 µmol/L and patients in remission averaging ~230 µmol/L. Serum uric acid in healthy controls was ~290 µmol/L.[41] Conversion factor: 1 mg/dL=59.48 µmol/L[20]
A 1998 study completed a statistical analysis of 20 million patient records, comparing serum uric acid values in patients with gout and patients with multiple sclerosis. Almost no overlap between the groups was found.[42]
Uric acid has been successfully used in the treatment and prevention of the animal (murine) model of MS. A 2006 study found elevation of serum uric acid values in multiple sclerosis patients, by oral supplementation with inosine, resulted in lower relapse rates, and no adverse effects.[43]
Correcting low or deficient zinc levels can help elevate serum uric acid.[44] Inosine can be used to elevate uric acid levels.[41] Zn inhibits Cu absorption, helping to reduce the high Cu/Fe in some people with hypouricemia. Fe supplements can ensure adequate Fe reserves (ferritin above 25 ng/dl), also correcting the high Cu/Fe.
Uric acid may be a marker of oxidative stress,[45] and may have a potential therapeutic role as an antioxidant.[46] On the other hand, like other strong reducing substances such as ascorbate, uric acid can also act as a prooxidant,[47] particularly at elevated levels. Thus, it is unclear whether elevated levels of uric acid in diseases associated with oxidative stress such as stroke and atherosclerosis are a protective response or a primary cause.[48][49]
For example, some researchers propose hyperuricemia-induced oxidative stress is a cause of metabolic syndrome.[37][50] On the other hand, plasma uric acid levels correlate with longevity in primates and other mammals.[51] This is presumably a function of urate's antioxidant properties.[52]
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