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Aldehyde oxidases (AOXs) and xanthine oxidoreductase (XOR) are closely related enzymes with very similar primary structures comprising two identical subunits each of which contains four redox centers: one molybdopterin cofactor, one flavin adenine dinucleotide (oxidized form) molecule, and two iron–sulfur clusters. The enzymes, also referred to as molybdenum hydroxylases, catalyze both oxidation and reduction reactions and play a significant role in the metabolism of drugs and endobiotics including endogenous purines. Generally, oxidation reactions involve nucleophilic attack via a Mo–OH ligand at a carbon atom in N -heterocycles and aldehydes with electrons transferred ultimately to molecular oxygen or NAD + (nicotinamide adenine dinucleotide—the oxidized form). Reduction of oxygen can generate reactive oxygen species, which have been implicated in a variety of protective and pathophysiological functions. AOXs and XOR are widely distributed throughout the animal kingdom and probably originated from a single ancestor gene coding for a dehydrogenase form of XOR. While a single mammalian XOR is known, various mammalian AOX isoenzymes have been identified. The complement of active mammalian AOX genes varies from one in humans ( AOX1 ) to four in rodents ( AOX1 , AOX2 , AOX3 , and AOX4 ). In humans, the AOX1 and XOR genes are found on different arms of chromosome 2 and are both subject to complex regulation, the precise details of which have not yet been fully characterized. The 3D structures of bovine milk XOR, human AOX1, and mouse AOX3 are available and have provided valuable information on the catalytic mechanism of molybdenum hydroxylases. This chapter provides an overview of the current knowledge on the structure, evolution, and function of these highly complex enzymes. |
