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Uric Acid

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 a product of the metabolic breakdown of 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 including diabetes and the formation of ammonium acid urate kidney stones.

Contents

[edit] Chemistry

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 pKa1 is lower 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 at an oxygen [-OH] like carboxylic acids do. 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, while 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 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.[4]

[edit] Solubility

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.[7]

[edit] Biology

The enzyme [10]

In [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]

[edit] 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: [19]

[edit] Medicine

In human citation needed]

Reference ranges for blood tests, comparing blood content of uric acid (shown in yellow) with other constituents

[edit] High uric acid

High levels of uric acid is called hyperuricemia .

[edit] Causes of high uric acid

  • In many instances, people have elevated uric acid levels for hereditary reasons.
  • Diet may be a factor. High intake of dietary purine as well as fructose (and table sugar which is roughly 50% fructose) can cause increased levels of uric acid.[22]
  • Serum uric acid can be elevated due to reduced excretion by the kidneys.[23]
  • Fasting or rapid weight loss can temporarily elevate uric acid levels.
  • Iron (Fe) activates xanthine oxidase (XO) and copper (Cu) deactivates it, so as men accumulate Fe with age (citation needed]

[edit] Gout

Excess serum accumulation of uric acid in the blood can lead to a type of [26]

A study 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.[27]

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.[28]

One treatment for gout, in the 19th century, had been administration of [31]

[edit] Lesch-Nyhan syndrome

[33]

[edit] Cardiovascular disease

Although uric acid can act as an antioxidant, excess serum accumulation is often associated with [35]

[edit] Type 2 diabetes

The association of high serum uric acid with [37]

[edit] Metabolic syndrome

Hyperuricemia is associated with components of [27]

[edit] Uric acid stone formation

Saturation levels of uric acid in blood may result in one form of X-ray, and thus 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).[39]

[edit] Low uric acid

[edit] Causes of low uric acid

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.[40]

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.[41]

[edit] Multiple sclerosis

Lower serum values of uric acid have been associated with [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.[43]

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.[44]

[edit] Normalizing low uric acid

Correcting low or deficient zinc levels can help elevate serum uric acid.[42] 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.

[edit] Oxidative stress

Uric acid may be a marker of [49]

For example, some researchers propose hyperuricemia-induced oxidative stress is a cause of [52]

[edit] Sources

  • In humans, purines are excreted as uric acid. Purines are found in high amounts in animal food products, such as liver and sardines.[54]
  • Examples of high purine and Fe sources include: gravy.
  • Moderate intake of purine-containing food is not associated with an increased risk of gout.[55]

[edit] References

  1. ^ McCrudden, Francis H. (2008). Uric Acid. BiblioBazaar.
  2. ^ European Powder Diffraction Conference, EPDIC-9
  3. ^ Scheele, V. Q. Examen Chemicum Calculi Urinari, Opuscula, 1776, 2, 73.
  4. ^ Behrend, R. History of the uric acid synthesis. Justus Liebigs Ann. Chem. 1925, 441, 215.
  5. ^ C.R.C. 62nd Ed.
  6. ^ MERK Index, Ninth Ed.
  7. ^ Uric Acid, Francis H. McCrudden, page 58
  8. ^ Hille, R. Molybdenum-containing hydroxylases. ARCH BIOCHEM BIOPHYS 2004, 433, 107-116.
  9. ^ Hori, N.; Uehara, K.; Mikami, Y. Enzymic synthesis of 5-methyluridine from adenosine and thymine with high efficiency. Biosci. , Biotechnol. , Biochem. 1992, 56, 580-582.
  10. 17494796.
  11. http://library.med.utah.edu/NetBiochem/pupyr/pp.htm#Pu%20Catab.
  12. 5477017.
  13. ^ S. R. J. Maxwell, H. Thomason, D. Sandler, C. Leguen, M. A. Baxter, G. H. G. Thorpe, A. F. Jones, A. H. Barnett. “Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus” European Journal of Clinical Investigation (1997) 27, 484-490. Blackwell Science Ltd., retrieved from http://www3.interscience.wiley.com/journal/119145773/abstract
  14. http://www.jbc.org/cgi/reprint/175/2/727.
  15. 978-0-520-23854-1.
  16. ^ 18327257.
  17. 18834627.
  18. 19503597. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2683940/.
  19. 18327256.
  20. ^ SI Units for Clinical Data
  21. ^ AMA Manual of Style Web site. Units of measure conversion table. http://www.amamanualofstyle.com/oso/public/jama/si_conversion_table.html
  22. 17130256.
  23. ^ Mayo Clinic staff. (September 11, 2010). High uric acid level. Mayo Clinic. Retrieved April 24, 2011.
  24. ^ 17190309.
  25. ^ Banach, K.; Bojarska, E.; Kazimierczuk, Z.; Magnowska, L.; Bzowska, A. Kinetic Model of Oxidation Catalyzed by Xanthine Oxidase—The Final Enzyme in Degradation of Purine Nucleosides and Nucleotides. Nucleosides Nucleotides Nucleic Acids 2005, 24, 465-469.
  26. ^ “What is Gout: What Causes Gout?”. MedicalBug. 6 January 2012. http://www.medicalbug.com/what-is-gout-what-causes-gout/. Retrieved 6 May 2012.
  27. ^ 20693348.
  28. 16586130.
  29. 11838882.
  30. http://www.cks.nhs.uk/gout/background_information/causes_and_risk_factors#-291124
  31. ^ Okamoto, K.; Eger, B. T.; Nishino, T.; Pai, E. F.; Nishino, T. Mechanism of Inhibition of Xanthine Oxidoreductase by Allopurinol: Crystal Structure of Reduced Bovine Milk Xanthine Oxidoreductase Bound with Oxipurinol. Nucleosides Nucleotides Nucleic Acids 2008, 27, 888-893.
  32. 16908130.
  33. 15804753.
  34. ^ http://www.drproctor.com/crcpap2.htm. Retrieved 6 May 2012.
  35. ^ Uric Acid: Neuroprotective or Neurotoxic?
  36. 8315780.
  37. 17977935.
  38. ^ 16234313.
  39. 18635234.
  40. http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=925768.
  41. 15641045.
  42. ^ 11985629.
  43. 9435251. //www.ncbi.nlm.nih.gov/pmc/articles/PMC18479/.
  44. 17121380.
  45. 3777013.
  46. 8325534.
  47. 16375736.
  48. 4680784.
  49. 18369163.
  50. 15507132. //www.ncbi.nlm.nih.gov/pmc/articles/PMC529248/.
  51. 6532339.
  52. 6947260. //www.ncbi.nlm.nih.gov/pmc/articles/PMC349151/.
  53. ^ Gout Causes: List of Diet/Food Sources High or Low in Purine Content
  54. ^ Gout Diet / Low Purine Diet – Limit High Purine foods
  55. 15014182.

[edit] Further reading

  • Nakamura, T. (April 2008). [Historical review of gout and hyperuricemia investigations]. Nippon Rinsho 66 (4): 624-635. PubMed 18409506.

[edit] External links

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