Multiplicity and ligand specificity

Enzymes utilizing a molybdnemum cofactor are known throughout evolution. In mammals, five distinct molybdo-flavoenzymes have been identified: XOR; AOX; and aldehyde oxidase homologs 1-3 (AOH1, AOH2, and AOH3). XOR and AOX have been characterized in a variety of species, including humans, whereas AOH1, AOH2, and AOH3 appear to be important only in rodent and bird species. These five enzymes are the products of distinct genes.63 The substrate specificities of only AOX and XOR have been studied in detail and much less is known about the catalytic functions of AOH1-3. AOX and XOR exhibit ~50% amino acid homology and overlapping substrate specificities.

XOR catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and represents a key enzyme in the metabolism of purines. In most tissues, XOR exists in its dehydrogenase form, where the physiological electron acceptor is NAD+. A number of factors, including ischemia and the purification process itself, promote facile conversion to the oxidase form where the electron acceptor is oxygen. Consequently, this enzyme is associated strongly with the production of reactive oxygen species (ROS), such as hydroxyl radical and superoxide. The enzyme can also produce nitric oxide by reduction of nitrites, which has further stimulated interest in the enzyme from a toxicological viewpoint.64 Allopurinol is a diagnostic inhibitor of the enzyme. This drug is used clinically to treat hyperuricemia, following its metabolic conversion to oxypurinol, a tight binding inhibitor of XOR.61

Abundant levels of AOX are present in the liver where it metabolizes numerous drugs, including zaleplon and 6-mercaptopurine. Guanine derivatives based on aciclovir are useful antiviral agents, but are poorly absorbed after oral administration. Attempts to improve bioavailability have centered around 6-deoxy prodrugs, e.g., 6-deoxy penciclovir, which are bioactivated byAOX (orXOR). AOXalso plays an important role in the detoxification of potentially reactive iminium ions that can be generated by P450 or MAO, often from cyclic tertiary amines, e.g., nicotine.40 Menadione, isovanillin, and raloxifene are useful diagnostic inhibitors of AOX.65

5.07.2.4.2 Structure

AOR and XOR are large (~ 300 kDa) multimeric enzymes composed of two subunits. Each subunit contains one atom of molybdenum (Mo) in a pyranopterin complex, one FAD, and two Fe-S centers. All four centers can function as redox groups in the intramolecular transfer of electrons from a reducing substrate (electron donor) to an oxidizing substrate (electron acceptor). Several bacterial members of this enzyme family have been crystallized, indirectly lending insight into the structure and function of XOR and AOR.60

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