Uric acid displays lactam–lactim
tautomerism.[3]). Uric acid crystallizes in the lactam form,[4] with
computational chemistry also indicating that tautomer to be the most stable.[5]
Uric acid is a
diprotic acid with
pKa1 = 5.4 and pKa2 = 10.3.[6] Thus at physiological pH, urate predominates in solution.
In general, the water
solubility of uric acid and its
alkali metal and
alkaline 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 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.
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.[7][8][9]
Biochemistry
The enzyme
xanthine oxidase (XO)
catalyzes the formation of uric acid from
xanthine and
hypoxanthine. XO, which is found in mammals, functions primarily as a dehydrogenase and rarely as an oxidase, despite its name.[10]) Xanthine in turn is produced from other
purines. Xanthine oxidase is a large enzyme whose
active site consists of the metal
molybdenum bound to
sulfur and oxygen.[11] Uric acid is released in
hypoxic conditions (low oxygen saturation).[12]
Genetic and physiological diversity
Primates
In
humans uric acid (actually hydrogen urate ion) is the final
oxidation (breakdown) product of
purine metabolism and is excreted in urine, whereas in most other
mammals, the enzyme
uricase further oxidizes uric acid to
allantoin.[13] 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.[14] 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 hydrogen urate ion.[15]
Humans
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[16] (but see below for slightly different values). An individual can have serum values as high as 96 mg/L and not have gout.[17] 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.[18] 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 of
urea.[19]
Dogs
The
Dalmatian 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.[20]
Birds, reptiles and desert-dwelling mammals
In
birds and
reptiles, and in some desert-dwelling mammals (such as 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 the
urea cycle) or
ammonia, but has the advantages of reducing water loss and preventing dehydration.[21]
Invertebrates
Platynereis dumerilii, a marine
polychaete worm, uses uric acid as a sexual
pheromone. The female of the species releases uric acid into the water during
mating, which induces males to release sperm.[22]
Genetics
Although foods such as meat and seafood can elevate serum urate levels, genetic variation is a much greater contributor to high serum urate.[23][24] 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; and PDZK1.[25][26][27] GLUT9, encoded by the SLC2A9 gene, is known to transport both uric acid and
fructose.[18][28][29]
Myogenic
hyperuricemia, as a result of the
Purine Nucleotide Cycle running when ATP reservoirs in muscle cells are low, is a common pathophysiologic feature of
glycogenoses such as
GSD-III,
GSD-V and
GSD-VII, as they are
metabolic myopathies which impair the ability of ATP (energy) production for the muscle cells to use.[30] 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.[30] Excess AMP (adenosine monophosphate) is converted into uric acid.
In human
blood plasma, the
reference 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).[31] Uric acid concentrations in blood plasma above and below the normal range are known as, respectively,
hyperuricemia and
hypouricemia. Likewise, uric acid concentrations in urine above and below normal are known as
hyperuricosuria and
hypouricosuria. Uric acid levels in saliva may be associated with blood uric acid levels.[32]
High uric acid
Hyperuricemia (high levels of uric acid), which induces
gout, has various potential origins:
A 2011 survey in the United States indicated that 3.9% of the population had gout, whereas 21.4% had hyperuricemia without having symptoms.[40]
Excess blood uric acid (serum urate) can induce
gout,[41] a painful condition resulting from needle-like crystals of uric acid termed monosodium urate crystals[42] precipitating in
joints,
capillaries,
skin, and other tissues.[43] 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.[17]
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.[44] Purine-rich foods include liver, kidney, and sweetbreads, and certain types of seafood, including anchovies, herring, sardines, mussels, scallops, trout, haddock, mackerel, and tuna.[45] Moderate intake of purine-rich vegetables, however, is not associated with an increased risk of gout.[44]
One treatment for gout in the 19th century was administration of
lithium salts;[46] lithium urate is more soluble. Today, inflammation during attacks is more commonly treated with
NSAIDs,
colchicine, or
corticosteroids, and urate levels are managed with
allopurinol.[47] Allopurinol, which weakly inhibits xanthine oxidase, is an analog of hypoxanthine that is hydroxylated by
xanthine oxidoreductase at the 2-position to give oxipurinol.[48]
Tumor lysis syndrome
Tumor lysis syndrome, an emergency condition that may result from
blood cancers, produces high uric acid levels in blood when tumor cells release their contents into the blood, either spontaneously or following
chemotherapy.[38] Tumor lysis syndrome may lead to
acute kidney injury when uric acid crystals are deposited in the kidneys.[38] Treatment includes
hyperhydration to dilute and excrete uric acid via
urine,
rasburicase to reduce levels of poorly soluble uric acid in blood, or
allopurinol to inhibit
purinecatabolism from adding to uric acid levels.[38]
Lesch–Nyhan syndrome
Lesch–Nyhan syndrome, a rare inherited disorder, is also associated with high serum uric acid levels.[49] Spasticity, involuntary movement, and cognitive retardation as well as manifestations of gout are seen in this syndrome.[50]
Cardiovascular disease
Hyperuricemia is associated with an increase in
risk factors for
cardiovascular disease.[51] 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.[52]
Uric acid stone formation
Kidney stones can form through deposits of sodium urate microcrystals.[53]
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, so do not appear on an abdominal plain
X-ray.[54] Uric acid crystals can also promote the formation of
calcium oxalate stones, acting as "seed crystals".[55]
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.[58]Sevelamer, a drug indicated for prevention of
hyperphosphataemia in people with
chronic kidney failure, can significantly reduce serum uric acid.[59]
Multiple sclerosis
Meta-analysis of 10 case-control studies found that the serum uric acid levels of patients with
multiple sclerosis were significantly lower compared to those of healthy controls, possibly indicating a diagnostic
biomarker for multiple sclerosis.[60]
Normalizing low uric acid
Correcting low or deficient zinc levels can help elevate
serum uric acid.[61]
See also
Theacrine or 1,3,7,9-tetramethyluric acid, a purine alkaloid found in some teas
Uracil –
purinenucleobase named by Robert Behrend who was attempting to synthesize derivatives of uric acid
^Jiménez, V.; Alderete, J. B. (November 2005). "Theoretical calculations on the tautomerism of uric acid in gas phase and aqueous solution". Journal of Molecular Structure: THEOCHEM. 755 (1–3): 209–214.
doi:
10.1016/j.theochem.2005.08.001.
^McCrudden, F. H. (2008) [1905]. Uric Acid: The Chemistry, Physiology and Pathology of Uric Acid and the Physiologically Important Purin Bodies, with a Discussion of the Metabolism in Gout. Charleston, SC: BiblioBazaar.
ISBN978-0-554-61991-0.
^Baillie, J. K.; Bates, M. G.; Thompson, A. A.; Waring, W. S.; Partridge, R. W.; Schnopp, M. F.; Simpson, A.; Gulliver-Sloan, F.; Maxwell, S. R.; Webb, D. J. (May 2007). "Endogenous urate production augments plasma antioxidant capacity in healthy lowland subjects exposed to high altitude". Chest. 131 (5): 1473–1478.
doi:
10.1378/chest.06-2235.
PMID17494796.
^Maxwell, S. R. J.; Thomason, H.; Sandler, D.; Leguen, C.; Baxter, M. A.; Thorpe, G. H. G.; Jones, A. F.; Barnett, A. H. (1997). "Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus". European Journal of Clinical Investigation. 27 (6): 484–490.
doi:
10.1046/j.1365-2362.1997.1390687.x.
PMID9229228.
S2CID11773699.
^Braunwald, E., ed. (1987). Harrison's Principles of Internal Medicine (11th ed.). New York:
McGraw-Hill. p. A-3.
ISBN978-0-07-079454-2.
^
abTausche, A. K.; Unger, S.; Richter, K.; et al. (May 2006). "Hyperurikämie und Gicht" [Hyperuricemia and gout: diagnosis and therapy]. Der Internist (in German). 47 (5): 509–521.
doi:
10.1007/s00108-006-1578-y.
PMID16586130.
S2CID11480796.
^
abVitart, V.; Rudan, I.; Hayward, C.; et al. (April 2008). "SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout". Nature Genetics. 40 (4): 437–442.
doi:
10.1038/ng.106.
PMID18327257.
S2CID6720464.
^Zeeck, E.; Harder, T.; Beckmann, M. (1998). "Uric acid: the sperm-release pheromone of the marine polychaete Platynereis dumerilii". Journal of Chemical Ecology. 24 (1): 13–22.
doi:
10.1023/A:1022328610423.
S2CID42318049.
^Zhao, J; Huang, Y (2015). "Salivary uric acid as a noninvasive biomarker for monitoring the efficacy of urate-lowering therapy in a patient with chronic gouty arthropathy". Clinica Chimica Acta. 450: 115–20.
doi:
10.1016/j.cca.2015.08.005.
PMID26276048.
^Howard, A. N. (1981). "The historical development, efficacy and safety of very-low-calorie diets". International Journal of Obesity. 5 (3): 195–208.
PMID7024153.
^Coffee, Carole J. (1999). Quick Look Medicine: Metabolism. Hayes Barton Press. pp. 176–177.
ISBN1-59377-192-4.
^Li, R.; Yu, K.; Li, C. (2018). "Dietary factors and risk of gout and hyperuricemia: a meta-analysis and systematic review". Asia Pacific Journal of Clinical Nutrition. 27 (6): 1344–1356.
doi:
10.6133/apjcn.201811_27(6).0022.
PMID30485934.
^Heinig, M.; Johnson, R. J. (December 2006). "Role of uric acid in hypertension, renal disease, and metabolic syndrome". Cleveland Clinic Journal of Medicine. 73 (12): 1059–1064.
doi:
10.3949/ccjm.73.12.1059.
PMID17190309.
S2CID45409308.
^Luo, Y. C.; Do, J. S.; Liu, C. C. (October 2006). "An amperometric uric acid biosensor based on modified Ir–C electrode". Biosensors & Bioelectronics. 22 (4): 482–488.
doi:
10.1016/j.bios.2006.07.013.
PMID16908130.
^Borghi, C.; Verardi, F. M.; Pareo, I.; Bentivenga, C.; Cicero, A. F. (2014). "Hyperuricemia and cardiovascular disease risk". Expert Review of Cardiovascular Therapy. 12 (10): 1219–1225.
doi:
10.1586/14779072.2014.957675.
PMID25192804.
S2CID42023170.
^Banach, K.; Bojarska, E.; Kazimierczuk, Z.; Magnowska, L.; Bzowska, A. (2005). "Kinetic Model of Oxidation Catalyzed by Xanthine Oxidase—The Final Enzyme in Degradation of Purine Nucleosides and Nucleotides". Nucleic Acids. 24 (5–7): 465–469.
doi:
10.1081/ncn-200060006.
PMID16247972.
S2CID42906456.
^Pak, C. Y. (September 2008). "Medical stone management: 35 years of advances". The Journal of Urology. 180 (3): 813–819.
doi:
10.1016/j.juro.2008.05.048.
PMID18635234.
^Wang, J. Y.; et al. (2012). "Predictive value of serum uric acid levels for the diagnosis of metabolic syndrome in adolescents". The Journal of Pediatrics. 161 (4): 753–6.e2.
doi:
10.1016/j.jpeds.2012.03.036.
PMID22575243.
^Hess, F. M.; King, J. C.; Margen, S. (1 December 1977). "Effect of low zinc intake and oral contraceptive agents on nitrogen utilization and clinical findings in young women". The Journal of Nutrition. 107 (12): 2219–2227.
doi:
10.1093/jn/107.12.2219.
PMID925768.