Xanthine Oxidoreductase

Abstract

A single gene product has been identified as responsible for the two catalytic activities, xanthine dehydrogenase, XDH (EC 1.1.1.204), and xanthine oxidase, XO (EC 1.2.3.2). Synthesized as XDH (ultimate electron acceptor NAD + ), the protein can be converted to XO (ultimate electron acceptor oxygen) either reversibly by oxidation of cysteine residues or irreversibly by proteolysis. Xanthine oxidoreductase (XOR) is a ubiquitous enzyme; its physiological role is the oxidation of hypoxanthine to xanthine and further to uric acid, although in vitro the enzyme's specificity is rather broad, accepting a large number of purines, pteridines, and aldehydes as substrates. XOR, in contrast to most other hydroxylases, incorporates water‐derived oxygen into its substrate. The electrons are transferred from xanthine to a Mopterin center and from there via two Fe 2 –S 2 clusters and FAD to NAD + or oxygen, respectively. The enzyme is the target of the antigout drug allopurinol; it is involved in hyperuricemia and xanthinuria and postulated to participate in postischemic reperfusion injury. Crystal structures have been determined for native and mutant XDHs and XOs from man, cow, rat, and Rhodobacter capsulatus . The conformational changes linked to the dehydrogenase/oxidase transition have been identified and interpreted. A structure‐based explanation for the catalytic mechanism is emerging.