Xanthine oxidase
Encyclopedia
Xanthine oxidase
Xanthine oxidase (XO (sometimes 'XAO'), a form of xanthine oxidoreductase that generates reactive oxygen species
. Is an enzyme
that catalyzes the oxidation of hypoxanthine
to xanthine
and can further catalyze the oxidation of xanthine to uric acid
. This enzyme plays an important role in the catabolism of purines in some species, including humans.
Xanthine oxidase is defined as an enzyme activity (EC 1.17.3.2). The same protein, which in humans has the HGNC approved gene symbol XDH, can also have xanthine dehydrogenase
activity (EC 1.17.1.4). Most of the protein in the liver exists in a form with xanthine dehydrogenase activity, but it can be converted to xanthine oxidase by reversible sulfhydryl oxidation or by irreversible proteolytic modification.
atoms, and 8 iron
atoms bound per enzymatic unit. The molybdenum atoms are contained as molybdopterin
cofactors and are the active sites of the enzyme. The iron atoms are part of [2Fe-2S] ferredoxin
iron-sulfur cluster
s and participate in electron transfer reactions.
), sulfur atoms and a terminal hydroxide
. In the reaction with xanthine to form uric acid, an oxygen atom is transferred from molybdenum to xanthine, whereby several intermediates are assumed to be involved. The reformation of the active molybdenum center occurs by the addition of water. Like other known molybdenum-containing oxidoreductases, the oxygen atom introduced to the substrate
by XO originates from water rather than from dioxygen (O2).
-producing enzyme found normally in serum
and the lungs, and its activity is increased during influenza A infection.
During severe liver damage, xanthine oxidase is released into the blood, so a blood assay for XO is a way to determine if liver
damage has happened.
As well, because xanthine oxidase is a metabolic pathway
for uric acid
formation, the xanthine oxidase inhibitor allopurinol
is used in the treatment of gout
. Since xanthine oxidase is involved in the metabolism of 6-mercaptopurine, caution should be taken before administering allopurinol and 6-mercaptopurine, or its prodrug azathioprine
, in conjunction.
Xanthinuria
is a rare genetic disorder
where the lack of xanthine oxidase leads to high concentration of xanthine in blood and can cause health problems such as renal failure
. There is no specific treatment, sufferers are advised by doctors to avoid foods high in purine
and to maintain a high fluid intake. Type I xanthinuria has been traced directly to mutations of the XDH gene which mediates xanthine oxidase activity. Type II xanthinuria may result from a failure of the mechanism which inserts sulfur into the active sites of xanthine oxidase and aldehyde oxidase
, a related enzyme with some overlapping activities (such as conversion of allopurinol
to oxypurinol
.
Inhibition of xanthine oxidase has been proposed as a mechanism for improving cardiovascular health.
Both xanthine oxidase and xanthine oxidoreductase
are also present in cornea
l epithelium and endothelium and may be involved in oxidative eye injury.
, oxypurinol
, and phytic acid
.
Xanthine oxidase (XO (sometimes 'XAO'), a form of xanthine oxidoreductase that generates reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
. Is an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that catalyzes the oxidation of hypoxanthine
Hypoxanthine
Hypoxanthine is a naturally occurring purine derivative. It is occasionally found as a constituent of nucleic acids where it is present in the anticodon of tRNA in the form of its nucleoside inosine. It has a tautomer known as 6-Hydroxypurine. Hypoxanthine is a necessary additive in certain cell,...
to xanthine
Xanthine
Xanthine , is a purine base found in most human body tissues and fluids and in other organisms. A number of stimulants are derived from xanthine, including caffeine and theobromine....
and can further catalyze the oxidation of xanthine to uric acid
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 created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
. This enzyme plays an important role in the catabolism of purines in some species, including humans.
Xanthine oxidase is defined as an enzyme activity (EC 1.17.3.2). The same protein, which in humans has the HGNC approved gene symbol XDH, can also have xanthine dehydrogenase
Xanthine dehydrogenase
Xanthine dehydrogenase, also known as XDH, is a protein that, in humans, is encoded by the XDH gene.-Function:Xanthine dehydrogenase belongs to the group of molybdenum-containing hydroxylases involved in the oxidative metabolism of purines. The enzyme is a homodimer...
activity (EC 1.17.1.4). Most of the protein in the liver exists in a form with xanthine dehydrogenase activity, but it can be converted to xanthine oxidase by reversible sulfhydryl oxidation or by irreversible proteolytic modification.
Reaction
The following chemical reactions are catalyzed by xanthine oxidase:- hypoxanthine + H2O + O2
xanthine + H2O2 - xanthine + H2O + O2
uric acid + H2O2 - Xanthine oxidase can also act on certain other purines, pterins, and aldehydes. For example, it efficiently converts 1-methylxanthine (a metabolite of caffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
) to 1-methyluric acid, but has little activity on 3-methylxanthine. - Under some circumstances it can produce superoxideSuperoxideA superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
ion RH + H2O + 2 O2
ROH + 2 O2- + 2 H+.
Protein structure
The protein is large, having a molecular weight of 270,000, and has 2 flavin molecules (bound as FAD), 2 molybdenumMolybdenum
Molybdenum , is a Group 6 chemical element with the symbol Mo and atomic number 42. The name is from Neo-Latin Molybdaenum, from Ancient Greek , meaning lead, itself proposed as a loanword from Anatolian Luvian and Lydian languages, since its ores were confused with lead ores...
atoms, and 8 iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
atoms bound per enzymatic unit. The molybdenum atoms are contained as molybdopterin
Molybdopterin
Molybdopterins, when reacted with molybdenum or tungsten in the form of molybdate or tungstate, are a class of cofactors found in most molybdenum and all tungsten enzymes...
cofactors and are the active sites of the enzyme. The iron atoms are part of [2Fe-2S] ferredoxin
Ferredoxin
Ferredoxins are iron-sulfur proteins that mediate electron transfer in a range of metabolic reactions. The term "ferredoxin" was coined by D.C. Wharton of the DuPont Co...
iron-sulfur cluster
Iron-sulfur cluster
For biological Fe-S clusters, see iron-sulfur proteins.Iron-sulfur clusters are ensembles of iron and sulfide centres. Fe-S clusters are most often discussed in the context of the biological role for iron-sulfur proteins. Many Fe-S clusters are known in the area of organometallic chemistry and as...
s and participate in electron transfer reactions.
Catalytic mechanism
The active site of XO is composed of a molybdopterin unit with the molybdenum atom also coordinated by terminal oxygen (oxoOxo
OXO was the first digital graphical computer game, a version of Tic-tac-toe.It is also the first puzzler game; As seen on Ginuess World Records 2010 Gamer's Edition.OXO Was first released in 1951, That makes it one of the oldest games standing....
), sulfur atoms and a terminal hydroxide
Hydroxide
Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and a hydrogen atom held together by a covalent bond, and carrying a negative electric charge. It is an important but usually minor constituent of water. It functions as a base, as a ligand, a nucleophile, and a...
. In the reaction with xanthine to form uric acid, an oxygen atom is transferred from molybdenum to xanthine, whereby several intermediates are assumed to be involved. The reformation of the active molybdenum center occurs by the addition of water. Like other known molybdenum-containing oxidoreductases, the oxygen atom introduced to the substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
by XO originates from water rather than from dioxygen (O2).
Clinical significance
Xanthine oxidase is a superoxideSuperoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
-producing enzyme found normally in serum
Serum
Serum may refer to:*Blood serum, a component of blood which is collected after coagulation.**Antiserum, blood serum with specific antibodies for passive immunity*Serous fluid, any clear bodily fluid*any drug derived from an animal's blood or serous fluid...
and the lungs, and its activity is increased during influenza A infection.
During severe liver damage, xanthine oxidase is released into the blood, so a blood assay for XO is a way to determine if liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
damage has happened.
As well, because xanthine oxidase is a metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
for uric acid
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 created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
formation, the xanthine oxidase inhibitor allopurinol
Allopurinol
Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
is used in the treatment of gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
. Since xanthine oxidase is involved in the metabolism of 6-mercaptopurine, caution should be taken before administering allopurinol and 6-mercaptopurine, or its prodrug azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
, in conjunction.
Xanthinuria
Xanthinuria
Xanthinuria, also known as xanthine oxidase deficiency, is a rare genetic disorder causing the accumulation of xanthine. It is caused by a deficiency of the enzyme xanthine oxidase.It was first formally characterized in 1954.-Causes:...
is a rare genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
where the lack of xanthine oxidase leads to high concentration of xanthine in blood and can cause health problems such as renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. There is no specific treatment, sufferers are advised by doctors to avoid foods high in purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
and to maintain a high fluid intake. Type I xanthinuria has been traced directly to mutations of the XDH gene which mediates xanthine oxidase activity. Type II xanthinuria may result from a failure of the mechanism which inserts sulfur into the active sites of xanthine oxidase and aldehyde oxidase
Aldehyde oxidase
Aldehyde oxidase is an enzyme which generates carboxylic acids from aldehydes. It catalyzes the conversion of an aldehyde in the presence of oxygen and water to an acid and hydrogen peroxide.* an aldehyde + H2O + O2 a carboxylate + H2O2 + H+...
, a related enzyme with some overlapping activities (such as conversion of allopurinol
Allopurinol
Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
to oxypurinol
Oxypurinol
Oxypurinol is an inhibitor of xanthine oxidase. It is an active metabolite of allopurinol and it is cleared renally. In cases of renal disease, this metabolite will accumulate to toxic levels....
.
Inhibition of xanthine oxidase has been proposed as a mechanism for improving cardiovascular health.
Both xanthine oxidase and xanthine oxidoreductase
Oxidoreductase
In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule to another...
are also present in cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
l epithelium and endothelium and may be involved in oxidative eye injury.
Inhibitors
Inhibitors of XO include allopurinolAllopurinol
Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
, oxypurinol
Oxypurinol
Oxypurinol is an inhibitor of xanthine oxidase. It is an active metabolite of allopurinol and it is cleared renally. In cases of renal disease, this metabolite will accumulate to toxic levels....
, and phytic acid
Phytic acid
Phytic acid is the principal storage form of phosphorus in many plant tissues, especially bran and seeds. Phytate is not digestible to humans or nonruminant animals, however, so it is not a source of either inositol or phosphate if eaten directly...
.