For this reason, oxipurinol is believed responsible for the majority of allopurinols effect. Mechanism of action
Allopurinol is a purine analog; it is a structural isomer of hypoxanthine (a naturally occurring purine in the body) and is an inhibitor of the enzyme xanthine oxidase. Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and xanthine, resulting in the production of uric acid, the product of human purine metabolism. In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribotides, hypoxanthine can be salvaged to the purine ribotides adenosine and guanosine monophosphates. Increased levels of these ribotides may cause feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis. Pharmacogenetics
The HLA-B*5801 allele is a genetic marker for allopurinol-induced severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801 allele frequencies of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1.0% and 0.5%, respectively. The increase in risk for developing allopurinol-induced SJS or TEN in individuals with the HLA-B*5801 allele (as compared to those who do not have this allele) is very high, ranging from a 40-fold to a 580-fold increase in risk, depending on ethnicity.
The molybdenum centre has a square pyramidal geometry and is distinguished from the xanthine oxidase family by the orientation of the oxo group facing downwards rather than up. Active site and mechanism
The active site of sulfite oxidase contains the molybdopterin cofactor and supports molybdenum in its highest oxidation state, +6 (MoVI). In the enzymes oxidized state, molybdenum is coordinated by a cysteine thiolate, the dithiolene group of molybdopterin, and two terminal oxygen atoms (oxos). Upon reacting with sulfite, one oxygen atom is transferred to sulfite to produce sulfate, and the molybdenum center is reduced by two electrons to MoIV. Water then displaces sulfate, and the removal of two protons (H+) and two electrons (e−) returns the active site to its original state. A key feature of this oxygen atom transfer enzyme is that the oxygen atom being transferred arises from water, not from dioxygen (O2). Electrons are passed one at a time from the molybdenum to the heme group which reacts with cytochrome c to reoxidize the enzyme. The electrons from this reaction enter the electron transport chain (ETC). This reaction is generally the rate limiting reaction. Upon reaction of the enzyme with sulfite, it is reduced by 2 electrons. The negative potential seen with re-reduction of the enzyme shows the oxidized state is favoured. Among the Mo enzyme classes, sulfite oxidase is the most easily oxidized. Although under low pH conditions the oxidative reaction become partially rate limiting. Deficiency
Sulfite oxidase is required to metabolize the sulfur-containing amino acids cysteine and methionine in foods.