Biochemistry, Xanthine Oxidase


Article Author:
Numan Aziz


Article Editor:
Radia Jamil


Editors In Chief:
Sisira Reddy
Joseph Nahas
CHOKKALINGAM SIVA


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
8/18/2019 8:51:21 AM

Introduction

Xanthine oxidase is the enzyme required to produce uric acid by the break down of purine nucleotides. The uric acid itself, as well as the reactive oxygen species released during the enzymatic reaction, can have detrimental effects on the body. Gout is a common condition that occurs due to elevated uric acid production via this mechanism. As a result, many drugs have been formed to combat gout, by inhibiting xanthine oxidase enzyme activity. Moreover, regulations of this enzyme have proven to be effective for anti-cancer purposes.[1]

Molecular

Xanthine oxidase is from the molybdenum family that contains flavin adenine dinucleotide, one molybdenum, and four iron-sulfur attachments with a net molecular mass of approximately 290kD. Xanthine oxidase along with xanthine dehydrogenase are zymogens that are cleaved by the enzyme trypsin to be activated.[2]

Function

Xanthine oxidase (XO) is an enzyme found in many species, including humans and primarily functions in the catabolism of purine nucleic acids. Through a series of reactions, the purines, guanine monophosphate (GMP) and adenosine monophosphate (AMP) get converted into either hypoxanthine or xanthine. The breakdown reaction of hypoxanthine and xanthine is catalyzed by xanthine oxidase into the uric acid. Uric acid then gets converted by the enzyme uricase into allantoin, a water-soluble molecule excreted in the urine. This enzyme is vital to mammalian cells as cell turnover is a constant process throughout the body, and endogenous or ingested purines are continually being degraded and renewed. Another form of xanthine oxidase is xanthine dehydrogenase (XD). Both forms are inter-convertible and catalyze the same reactions. However, they do differ in the cofactors used; where XO uses oxygen as a substrate, XD requires NADH to carry out the same reaction.[3][4][5]

The reaction carried out by XO reduces oxygen into a superoxide anion which eventually progresses into hydrogen peroxide. Hydrogen peroxide is a reactive oxygen species (ROS), the excess of which is toxic to individual cells. It also has links to aging and a multitude of conditions such as diabetes and neurodegenerative disorders such as Alzheimer disease.[6]

The product of xanthine oxidase activity, uric acid, has also proven to be harmful in previous literature. The urate behaves as a pro-oxidant and induces the formation of other radicals that have a tendency to oxidize lipid membranes, which explains the correlation between hyperuricemia and obesity. Reactive oxygen species naturally tend to damage cellular structures, DNA and proteins, and consequently, oxidative stress caused by uric acid also has links to hypertension, diabetes, kidney disease, and cardiovascular diseases. Cardiovascular health, being endemic in North America, is currently being studied extensively for the risk level associated with xanthine oxidase activity. The activity of xanthine oxidase can also be monitored in corneal epithelium. As such, the deduction is that free radical damage is related to an oxidate eye injury that may result from overactivity of xanthine oxidase.[7]

Pathophysiology

The deficiency of xanthine oxidase leads to a condition called hereditary xanthinuria type 1, attributed to a mutation in the XDH gene that leads to decreased amounts of xanthine oxidase production. Although rare, this condition can have detrimental effects on the individual, whereby a decreased metabolism of xanthine leads to elevated systemic levels of xanthine. The xanthine precipitates in the renal tubules and forms the rare xanthine kidney stones. If left untreated, this obstructs the renal parenchyma and can result in life-threatening renal failure. Patients also complain of recurrent episodes of muscle aches and joint pain. Patients with hereditary xanthuria type 1 are advised to limit their intake of proteins such as those found in meat products; this prevents the buildup of excess xanthine from protein breakdown and prevents the disease from worsening into a more severe state. Patients with type 2 of the condition have normal expression of the XDH gene, but the final protein product fails to incorporate a sulfur molecule into its core, which ultimately limits the functionality of the protein. The symptoms of type 1 and type 2 hereditary xanthinuria are the same.  Studies have also indicated that patients with higher levels of XDH gene expression have a direct link to the survival rates of certain cancers. For example, patients with lung adenocarcinoma and a higher expression of the XDH gene had lower survival rates. Although this area is not particularly well studied, further research in this field is warranted.[8]

Clinical Significance

Manipulation of xanthine oxidase within the body has a plethora of pharmacological indications, most significant being that of treating the symptoms of gout. Gout is a painful condition in which there is excess uric acid metabolism. The excess uric acid then precipitates and forms monosodium urate crystals within the joints and the kidney, causing painful gouty arthritis and uric acid kidney stones, respectively. The pharmacological interventions used widely for prevention of gout involves drugs such as allopurinol and febuxostat. These drugs achieve the desired effect by inhibiting xanthine oxidase, which limits the conversion of purine products and eventually leads to decreased production of uric acid within the body and limitation of gout symptoms.[9]

Additionally, xanthine oxidase has inhibitory effects on certain drugs. These include the antimetabolite class of cancer drugs like azathioprine and 6-mercaptopurine, both of which are metabolized by xanthine oxidase. Concurrent use of XO inhibitors and the anti-cancer drugs leads to excess anti-cancer drug accumulation in the body due to the limited breakdown, and subsequent dose reductions then become mandatory. If there is poor dose and drug regimen management, anti-cancer drug overdose and associated toxic adverse effects can occur.[10]

As aforementioned above, higher activity of xanthine oxidase correlates with an elevated risk of cardiovascular disease along with other pathologies. As such, it has been postulated and should be further studied, that patients on xanthine oxidase inhibitors such as allopurinol who display decreased enzymatic activity, can potentially have lowered risks of cardiovascular and other pathological conditions. This effect can be tied into liver diseases as well as the presence of xanthine oxidase in greater quantities has also been seen in patients with severe liver injury. Although the reason for the correlation is not definitive as of yet, expectations are that the greater the severity of liver diseases, the higher the levels of xanthine oxidase will be in the serum. There remain more specific tests to evaluate liver function, but xanthine oxidase levels can also be an indicator of hepatic health.[11]


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Biochemistry, Xanthine Oxidase - Questions

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A 24-year-old male presents with repeated episodes of pain in the left great toe over the past year. The patient indicates the pain is exacerbated after meals rich in protein and after alcohol use. Once the diagnosis of gout is established, the patient is started on the first line treatment for chronic gout. What is the mechanism of action of this drug?



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A 16-year-old female comes into the office with a history of abdominal pain, hematuria, and right flank pain for the past three days. She has no past medical history of similar symptoms or any surgical history. Her blood pressure on examination is 126/84. An ultrasound examination revealed renal calculi obstructing the parenchyma. Post-lithotripsy, brick-red calculi are passed in the urine. The patient is informed that his condition can eventually lead to renal failure. Which of the following enzyme deficiency is causing this patient's condition?



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A 65-year-old male presents with a 2-day history of jaundice, malaise, and fever. Lab results show elevated liver enzymes. He is currently on immunosuppression regimen for a kidney transplant with azathioprine. 2 weeks ago he began treatment for gout. What is the reason for this patient's elevated liver enzymes?



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A 24-year-old male presents with recurrent episodes of pain and swelling of the first metatarsal. After a detailed physical examination and relevant laboratory tests, the patient is placed on a medication that prevents the synthesis of uric acid from its precursor. Which of the following would be elevated in the serum of this patient due to this medication?



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A 32-year-old male presents to the office with a painful great toe. He has had similar episodes in the past, but this one is particularly painful. All vitals were normal and physical examination was normal except for an enlarged and tender right great toe. Serum studies reveal elevated uric acid levels. Which of the following leads to an acute exacerbation of this patient's symptoms?



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Biochemistry, Xanthine Oxidase - References

References

Battelli MG,Polito L,Bortolotti M,Bolognesi A, Xanthine Oxidoreductase in Drug Metabolism: Beyond a Role as a Detoxifying Enzyme. Current medicinal chemistry. 2016;     [PubMed]
Okamoto K,Matsumoto K,Hille R,Eger BT,Pai EF,Nishino T, The crystal structure of xanthine oxidoreductase during catalysis: implications for reaction mechanism and enzyme inhibition. Proceedings of the National Academy of Sciences of the United States of America. 2004 May 25;     [PubMed]
Pacher P,Nivorozhkin A,Szabó C, Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacological reviews. 2006 Mar;     [PubMed]
El Ridi R,Tallima H, Physiological functions and pathogenic potential of uric acid: A review. Journal of advanced research. 2017 Sep;     [PubMed]
Wang CH,Zhang C,Xing XH, Xanthine dehydrogenase: An old enzyme with new knowledge and prospects. Bioengineered. 2016 Nov;     [PubMed]
Battelli MG,Polito L,Bortolotti M,Bolognesi A, Xanthine Oxidoreductase-Derived Reactive Species: Physiological and Pathological Effects. Oxidative medicine and cellular longevity. 2016;     [PubMed]
de Oliveira EP,Burini RC, High plasma uric acid concentration: causes and consequences. Diabetology     [PubMed]
Furman E,Hooijberg EH,Leidinger E,Zedinger C,Giger U,Leidinger J, Hereditary xanthinuria and urolithiasis in a domestic shorthair cat. Comparative clinical pathology. 2015 Nov 1;     [PubMed]
Jang IT,Hyun SH,Shin JW,Lee YH,Ji JH,Lee JS, Characterization of an Anti-gout Xanthine Oxidase Inhibitor from Pleurotus ostreatus. Mycobiology. 2014 Sep;     [PubMed]
Bradford K,Shih DQ, Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease. World journal of gastroenterology. 2011 Oct 7;     [PubMed]
Stirpe F,Ravaioli M,Battelli MG,Musiani S,Grazi GL, Xanthine oxidoreductase activity in human liver disease. The American journal of gastroenterology. 2002 Aug     [PubMed]

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