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Uric acid
From Wikipedia, the free encyclopedia
Uric acid (or urate) is a heterocyclic Uric acid
compound of carbon, nitrogen, oxygen, and
hydrogen with the formula C5H4N4O3.
Contents
IUPAC name
7,9dihydro1Hpurine
1 Chemistry
2,6,8(3H)trione
1.1 Solubility of uric acid and its
Other names
salts
2,6,8 Trioxypurine
2 Biology Identifiers
3 Genetics CAS number 69932
4 Medicine PubChem 1175
4.1 High uric acid ChemSpider 1142
4.1.1 Gout EC number 2007207
4.1.2 LeschNyhan KEGG C00366
syndrome SMILES
4.1.3 Cardiovascular
C12NC(=O)NC(=O)C=2NC(=O)N1
disease
InChI
4.1.4 Diabetes
4.1.5 Metabolic syndrome 1/C5H4N4O3
4.1.6 Uric acid stone /c10312(74(11)61)85(12)93
formation /h(H4,6,7,8,9,10,11,12)/f/h69H[1]
4.1.7 Causes of high uric Properties
acid Molecular formula C5H4N4O3
Molar mass 168g/mol
4.2 Low uric acid Appearance White Crystals
4.2.1 Multiple sclerosis
Density 1.87
4.2.2 Causes of low uric
Melting point
acid decomposes on heating
4.2.3 Normalizing low uric
acid Boiling point
N/A
4.3 Oxidative stress
5 Sources of uric acid Solubility in water Slightly
6 Other uric acid facts Acidity (pKa) 5.8
7 See also (what is this?) (verify) (http://en.wikipedia.org
8 References /w/index.php?title=Uric_acid&diff=cur&oldid=268443488)
Except where noted otherwise, data are given for materials in
9 External links
their standard state (at 25 °C, 100 kPa)
Infobox references
Chemistry
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Uric acid is a diprotic acid with pKa1=5.4 and pKa2=10.3.[2] 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 hydrolyse 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 in the same manner as do
carboxylic acids. XRay diffraction studies on the hydrogen urate ion in crystals of ammomium hydrogen
urate, formed in vivo as gouty deposits, revealed that the ketooxygen in the 2 position of a tautomer of the
purine structure existed as a hydroxyl group and that the two flanking nitrogen atoms at the 1 and 3
positions shared the ionic charge in the six membered piresonancestabilized ring.[3]
Thus, whereas most organic acids are deprotonated by the ionization of a polar hydrogentooxygen bond,
usually accompanied by some form of resonance stabilization (resulting in a carboxylate ion), this acid is
deprotonated at a nitrogen atom and uses a tautomeric keto/hydroxy group as an electronwithdrawing
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
piresonance 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".)
Solubility of uric acid and its salts
Generally the solubilities of uric acid, its Alkali and Alkali Earth Metal salts in water are rather low and all
exhibit greater solubility in hot water than cold allowing for easy recrystallization. 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.
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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.[4][5][6]
Biology
Uric acid is produced by xanthine oxidase from xanthine and hypoxanthine, which in turn are produced
from purine. Uric acid is more toxic to tissues than either xanthine or hypoxanthine.[citation needed] Uric
acid is released in hypoxic conditions.[7]
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.[8] The loss of uricase in higher primates parallels the similar loss of the ability to synthesize
ascorbic acid.[9] 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.[10] The
Dalmatian dog has a genetic defect in uric acid uptake by the liver, resulting in decreased conversion to
allantoin, so this breed excretes uric acid, and not allantoin, in the urine.[11]
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.[12]
In humans, about 70% of daily uric acid disposal occurs via the kidneys, and in 525% of humans impaired
renal (kidney) excretion leads to hyperuricemia.[13]
Genetics
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.[14][15] SLC2A9 is known to transport both uric acid and
fructose.[13][16]
Medicine
In human blood plasma, the reference range of uric acid is between 3.6 mg/dL (~214µmol/L) and
8.3 mg/dL (~494µmol/L) (1 mg/dL=59.48 µmol/L).[17] This range is considered normal by the American
Medical Association. 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.[citation needed]
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Reference ranges for blood tests, comparing blood content of uric acid (shown in
yellow) with other constituents
High uric acid
Gout
Excess serum accumulation of uric acid can lead to a type of arthritis known as gout.[18] This painful
condition is the result of needlelike crystals of uric acid precipitating in joints and capillaries.
Elevated serum uric acid (hyperuricemia) can result from high intake of purinerich foods, and/or impaired
excretion by the kidneys. 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 xray or CT scan. Their presence must be diagnosed by ultrasound for this reason. Very
large stones may be detected on xray by their displacement of the surrounding kidney tissues. Some
patients with gout eventually get uric kidney stones.[citation needed]
Gout can occur where serum uric acid levels are as low as 6 mg/dL (~357µmol/L), but an individual can
have serum values as high as 9.6 mg/dL (~565µmol/L) and not have gout.[19]
One treatment for gout has been administration of Lithium salts; lithium urate is more soluble.
LeschNyhan syndrome
LeschNyhan syndrome, an extremely rare inherited disorder, is also associated with very high serum uric
acid levels.[20]
Spasticity, involuntary movement and cognitive retardation as well as manifestations of gout are seen in
cases of this syndrome.[21]
Cardiovascular disease
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.[18]
Diabetes
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.[22] However, it was shown in a prospective followup study that high
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serum uric acid is associated with higher risk of type 2 diabetes independent of obesity, dyslipidemia, and
hypertension.[23]
Metabolic syndrome
Hyperuricemia is associated with components of metabolic syndrome and it has been debated for a while to
be a component of it. A study has suggested that fructoseinduced hyperuricemia may play a pathogenic
role in the metabolic syndrome.[24] This is consistent with the increased consumption in recent decades of
fructosecontaining beverages (such as fruit juices and soft drinks sweetened with sugar and highfructose
corn syrup) and the epidemic of diabetes and obesity.
Uric acid stone formation
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 promotor 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).[25]
Causes of high uric acid
In many instances, people have elevated uric acid levels for hereditary reasons.
Diet may be a factor: as mentioned above in Metabolic Syndrome, fructose (and sucrose) can cause
increased levels of uric acid. Eating large amounts of sea salt can cause increased levels of uric
acid.[citation needed] (Medical consultation is recommended before using large quantities of sea salt in
daily cooking.[citation needed])
Serum uric acid can be elevated due to reduced excretion by the kidneys
Serum uric acid can be elevated due to high intake of dietary purine.[citation needed]
Fe activates xanthine oxidase (XO) and Cu deactivates it, so that as men accumulate Fe with age
(ferritin levels rise above 45 ng/dl) and Cu levels decline as testosterone levels drop with age
(testosterone increases Cu half life), eventually the high Fe/Cu results in more active XO and higher
urate levels. Excess Fe can be eliminated through phlebotomy (blood donation) and low Cu can be
corrected through daily intake of 2 mg Cu per day, reducing urate levels.
Low uric acid
Multiple sclerosis
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Lower serum values of uric acid have been associated with Multiple Sclerosis. Multiple sclerosis (MS)
patients have been found to have serum levels ~194µmol/L, with patients in relapse averaging ~160µmol/L
and patients in remission averaging ~230µmol/L. Serum uric acid in healthy controls was ~290µmol/L.[26]
Conversion factor: 1 mg/dL=59.48 µmol/L[17]
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.[27]
Uric acid has been successfully used in the treatment and prevention of the animal (murine) model of MS.
A 2006 study found that elevation of serum uric acid values in multiple sclerosis patients, by oral
supplementation with inosine, resulted in lower relapse rates, and no adverse effects.[28]
Causes of low uric acid
Low uric acid (hypouricemia) can have numerous causes.[citation needed]
Low dietary zinc intakes cause lower uric acid levels. This effect can be even more pronounced in women
taking oral contraceptive medication.[29]
Xanthine oxidase is an FeMo enzyme, so people with Fe deficiency (the most cammon 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 Xanthine
oxidase are replaced with Cu atoms. Accordingly, people with high Cu/Fe can experience hypouricemia
anc vitamin C deficiency, resulting in oxidative damage. Since estrogen increases the half life of Cu,
women with very high estrogen levels and intense blood los 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.[30]
Normalizing low uric acid
Correcting low or deficient zinc levels can help elevate serum uric acid.[31] Inosine can be used to elevate
uric acid levels.[26] 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.
Oxidative stress
Uric acid may be a marker of oxidative stress,[32] and may have a potential therapeutic role as an
antioxidant.[33] On the other hand, like other strong reducing substances such as ascorbate, uric acid can
also act as a prooxidant,[34] 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.[35][36]
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For example, some researchers propose that hyperuricemiainduced oxidative stress is a cause of metabolic
syndrome.[24][37] On the other hand, plasma uric acid levels correlate with longevity in primates and other
mammals.[38] This is presumably a function of urate's antioxidant properties.[citation needed]
Sources of uric acid
In humans Purines are excreted as uric acid. Purines are found in high amounts in animal food
products, such as liver and sardines.[39] A moderate amount of purine is also contained in beef, pork,
poultry, fish and seafood, asparagus, cauliflower, spinach, mushrooms, green peas, lentils, dried peas,
beans, oatmeal, wheat bran and wheat germ.[40]
Examples of high purine and Fe sources include: sweetbreads, anchovies, sardines, liver, beef
kidneys, brains, meat extracts (e.g., Oxo, Bovril), herring, mackerel, scallops, game meats, and gravy.
[citation needed]
Moderate intake of purinecontaining food is not associated with an increased risk of gout.[41]
Other uric acid facts
The high nitrogen content of uric acid makes guano a useful agricultural fertilizer.[citation needed]
The crystalline form of uric acid is used as a reflector in certain species of fireflies.[citation needed]
The uric acid in urine can also dry in a baby's diaper to form a pinkish powder that is harmless.
[citation needed]
Urate is being researched for its possible antioxidant properties in treating Parkinson's disease.[42]
See also
Hyperuricemia
References
1. ^ "Uric Acid." Biological Magnetic Resonance Simpson, F. GulliverSloan, S.R. Maxwell, D.J.
Data Bank. Indicator Information Webb (200705). "Endogenous urate production
(http://www.bmrb.wisc.edu/metabolomics augments plasma antioxidant capacity in healthy
/gen_metab_summary_5.php?molName=uric_acid#INCHI) lowland subjects exposed to high altitude". Chest
Retrieved on 18 February 2008. 131 (5): 1473–1478. doi:10.1378/chest.062235
2. ^ Uric Acid, Francis H. McCrudden (http://dx.doi.org/10.1378%2Fchest.062235) .
3. ^ European Powder Diffraction Conference, PMID 17494796 (http://www.ncbi.nlm.nih.gov
EPDIC9 /pubmed/17494796) .
4. ^ C.R.C. 62nd Ed. 8. ^ Angstadt, Carol N. (19971204). Purine and
5. ^ MERK Index, Ninth Ed. Pyrimidine Metabolism: Purine Catabolism.
6. ^ Uric Acid, Francis H. McCrudden, page 58 NetBiochem, 4 December 1997. Retrieved from
7. ^ Baillie, J.K.; M.G. Bates, A.A. Thompson, W.S. http://library.med.utah.edu/NetBiochem/pupyr
Waring, R.W. Partridge, M.F. Schnopp, A. /pp.htm#Pu%20Catab.
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mellitus: The urate redox shuttle" (http://www.dietaryfiberfood.com/purine
(http://www.pubmedcentral.nih.gov food.php)
/articlerender.fcgi?tool=pmcentrez&artid=529248) 40. ^ Gout Diet / Low Purine Diet Limit High Purine
. Nutrition & Metabolism 1 (1): 10. foods (http://www.healthcastle.com/gout.shtml)
doi:10.1186/17437075110 (http://dx.doi.org 41. ^ Choi HK, Atkinson K, Karlson EW, Willett W,
/10.1186%2F17437075110) . PMID 15507132 Curhan G (March 2004). "Purinerich foods, dairy
(http://www.ncbi.nlm.nih.gov/pubmed/15507132) . and protein intake, and the risk of gout in men".
38. ^ Cutler RG (December 1984). "Urate and The New England Journal of Medicine 350 (11):
ascorbate: their possible roles as antioxidants in 1093–103. doi:10.1056/NEJMoa035700
determining longevity of mammalian species". (http://dx.doi.org/10.1056%2FNEJMoa035700) .
Archives of Gerontology and Geriatrics 3 (4): PMID 15014182 (http://www.ncbi.nlm.nih.gov
321–48. doi:10.1016/01674943(84)900335 /pubmed/15014182) .
(http://dx.doi.org 42. ^ Edelson, Ed (20091013). Common Antioxidant
/10.1016%2F01674943%2884%29900335) . Might Slow Parkinson's. HealthDay, 13 October
PMID 6532339 (http://www.ncbi.nlm.nih.gov 2009. Retrieved on 24 October 2009 from
/pubmed/6532339) . http://news.yahoo.com/s/hsn/20091021/hl_hsn
39. ^ Gout Causes: List of Diet/Food Sources High or /commonantioxidantmightslowparkinsons.
Low in Purine Content
External links
MedlinePlus (http://www.nlm.nih.gov/medlineplus/ency/article/003476.htm) Uric Acid Test
International Kidney Stone Institute (http://www.iksi.org)
Purine content in food (http://www.dietaryfiberfood.com/purinefood.php)
Retrieved from "http://en.wikipedia.org/wiki/Uric_acid"
Categories: Uric acid | Nitrogen metabolism | Organic acids
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