Xanthine oxidase catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid as follows

The enzyme is well-suited to carry out the catalysis of these oxidative reactions, containing as it does four redox-active sites: molybdenum, flavin adenine dinucleotide (FAD) and a pair of iron-sulfur centers of the ferredoxin type (Fe2S2). The purine substrates interact with the enzyme at the molybdenum site of xanthine oxidase and oxygen at the flavin site. The two metabolic reactions above Constitute the final steps of purine catabolism in primates and as such play an important role in determining the in vivo steady state levels of the various purines, particularly that of uric acid. The introduction of potent inhibitors of xanthine oxidase has proven a clinically effective way to control the hyperuricemia associated with gout (Elion et al., 1963; Duggan et al., 1975; cf. Rundles et al., 1969, for a review) and attenuate the activity of mercaptopurinol and other antileukemic drugs (Rundles et al., 19631. In addition, in vitro studies on the mechanism of action of these compounds have shed considerable light on the properties of the enzyme itself (e.g. Massey et al., 1970a,b). This review will concern itself primarily with such in vitro studies, and the reader is referred to the review by Rundles et al., for clinical considerations. Two review articles onthe general properties of xanthine oxidase have appeared recently (Massey, 1973; Bray, 19751. Potent inhibitors of xanthine oxidase can be divided into two broad categories: (11 molecules which are analogs of the purine substrates to a greater or lesser extent and (2) molecules which bear no particular structural relationship to the physiological substrates. The former group consists of pyrazolo[3,4-d]pyrimidines (alloxanthine being the most important among them), pterins such as 6-pteridylaldehyde, and certain other aromatic heterocycles. Included in the latter group are cyanide, arsenite, and methanol, compounds which do not inhibit xanthine oxidase exclusively, but nonetheless interact very specifically with the enzyme. Both classes of inhibitors act at or very near the molybdenum site of the enzyme, or with the active site cyanolysable sulfur atom (cf. Section 3.11, and interfere with the reaction of enzyme with the reducing substrates (hydroxypurines) rather than oxygen. The following discussion will deal first with the purine analogs, about which a good deal is known, and then take up the second class of inhibitors, about which a good deal less is understood.