Sandbox Reserved 1452

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This Sandbox is Reserved from Jan 22 through May 22, 2018 for use in the course Biochemistry II taught by Jason Telford at the Maryville University, St. Louis, Missouri, USA. This reservation includes Sandbox Reserved 1446 through Sandbox Reserved 1455.

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Uricase

spinqualitylabelsall models Caption for this structure Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Uricase is a hepatic enzyme meaning it is located in the liver and converts uric acid into allantoin. Allantoin is more efficiently excreted by the kidney because of how water soluble it is. However, in humans, a frameshift mutation during evolution affected the activity of the gene that encodes for uricase. Function It is an enzyme that converts uric acid to allantoin. Allantoin is much more soluble than uric acid, and passes harmlessly from the body. Unfortunately, during evolution, humans have lost the ability to produce uricase. The detailed mechanism consists or this copper binding enzyme catalyzing the oxidation or uric acid to .5-hydroxyisourate and hydrogen peroxide followed by the hydrolysis and decarboxylation leading to the formation of the desired product, allantoin. Allantoin is significantly more water soluble than uric acid and easily excreted in urine. Disease If there is some damage to uricase or if it is absent in the body, it may be detrimental. Without functioning uricase, there will be an excess amount of insoluble uric acid in the body which leads to a disease called gout. Gout is a form of inflammatory arthritis that develops in people who have high levels of uric acid in the blood. The acid forms needle-like crystals in joints and causes sudden, severe episodes of pain, redness, and swelling. Uric acid is a waste material made by the breakdown of purines. Purines are found in foods high in protein. Gout occurs when uric acid accumulates which happens when there is more intake of uric acid than excreted uric acid. This leads to acute gout. The immune system recognizes it as a foreign product and attacks it. This will then lead to inflammation. The joint could be damaged or there could be bone erosion when the join is attacked. Cure There are many natural treatment options which include a decrease of purine intake, exercise, decrease smoking and alcohol intake, use of cherry juice (eliminate excess uric acid in blood). Another type of treatment available is gout therapy and medication. Pegloticase is a porcine uricase which is approved by the FDA for treatment of patients with gout. It must be administered by intravenous infusion every two weeks. Corticosteroids can also be taken by mouth or injected into an inflamed joint to relieve the pain and swelling of an acute gout attack. Corticosteroids and adrenocorticotropic hormones usually start working within 24 hours after you begin taking them. Relevance Uricase is an enzyme that catalyzes the conversion or uric acid to allantoin. Uric acid is an acidic waste product that your body passes through urine. It is a normal byproduct of the breakdown of foods that contain purines. Normally, the kidneys filter out uric acid from your blood; if too much builds up, it can lower the pH of your blood and urine and lead to a painful joint condition called gout and other complications. Interestingly, humans have naturally selected to terminate uricase. Because of the absence of uricase in humans, we may go through many complications caused by uric acid build up. Scientists are studying why natural selection would allow the accumulation of uric acid even though there are psychological complications of crystalized monosodium urate acutely causing liver and kidney damage or chronically causing gout. Structural highlights Uricase is mainly located in the liver where it forms an elctron dense crystalline core in peroxisomes. It is a tetramer of identical subunits each containing copper binding sites. X-ray crystallography shows that uric acid binds to the active site as a monoanion and is deprotonated as a dianion which is then stabilized by <scene name='77/778332/1vax/1'>Arg/Glu 176 and Gln 228.</scene> Uricase can be inhibited by both cyanide and chloride ions. Oxonate competitively inhibits uricase. This is uricase without a ligand. You can view uricase with a ligand here.

References

Bonifacio, and Vicente. “Uric Acid and Evolution | Rheumatology | Oxford Academic.” OUP Academic, Oxford University Press, 13 July 2010, academic.oup.com/rheumatology/article/49/11/2010/1785765.

Gabison, et al. “Near-Atomic Resolution Structures of Urate Oxidase Complexed with Its Substrate and Analogues: the Protonation State of the Ligand.” Acta Crystallogr.,Sect.D, www.rcsb.org/structure/3L8W.

Kratzer, James T., et al. “Evolutionary History and Metabolic Insights of Ancient Mammalian Uricases.” PNAS, National Academy of Sciences, 11 Mar. 2014, www.pnas.org/content/111/10/3763.short.

Ortlund, E.o., and M.n. Murphy. “Evolutionary History and Metabolic Insights of Ancient Mammalian Uricases.” Evolutionary History and Metabolic Insights of Ancient Mammalian Uricases, 2014, doi:10.2210/pdb4mb8/pdb.