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The Thermodynamics of Xanthine O x i d o r e d u c t a s e Catalysis

Xanthine oxidoreductase is a complex enzyme found in a wide range of organisms. Recent interest in this enzyme stems from its ability to produce reactive oxygen species under a range of conditions. It is found as a homodimer, each unit containing a molybdopterin cofactor, two iron sulfur centers, and FAD. The enzyme can exist in two forms that differ primarily in their oxidizing substrate specificity. The dehydrogenase form preferentially utilizes NAD+ as an electron acceptor but is able to donate electrons to molecular oxygen. Xanthine dehydrogenase from mammalian sources can be converted to an oxidase form that readily donates electrons to molecular oxygen, but does not reduce NAD+. The catalytic mechanism of both forms of the enzyme can be described in terms of a rapid equilibrium model in which reducing equivalents are distributed rapidly between the different redox centers of the enzyme on the basis of their midpoint potentials. The present commentary gives a brief overview of the literature concerning the rapid equilibrium model and the differences between the two enzyme forms. N A D H is also discussed in terms of an alternative to xanthine or hypoxanthine as an electron donor. Antiox. Redox Signal. 1, 371-379. I N T R O D U C T I O N Xanthine oxidoreductase (XOR) is a widely distributed enzyme found in organisms ranging from bacteria (Leimkuhler et al, 1998) to humans (Kooij et al, 1992), higher plants (Nguyen, 1986; Mendel and Schwarz, 1999), and invertebrates (Doyle et al, 1996). The action of xanthine oxidoreductase was first observed in 1902 when it was shown that fresh milk could decolorize methylene blue in the presence of formaldehyde (Schardinger, 1902). The enzyme was then shown to convert hypoxanthine and xanthine to urate in the presence of oxygen or anaerobically in the presence of methylene blue (Morgan et al, 1922). The high availability of xanthine oxidase from bovine milk has led to a wide body of research concerning its action. The enzyme from mammalian sources exists in two interconvertible forms, an oxidase form (XO) and a dehydrogenase form (XDH). It is a homodimer, with each subunit containing a molybdopterin cofactor, two iron sulfur centers, and one FAD. A wide range of reducing substiates can donate electrons to the molybdopterin cofactor (Hille, 1994), including purines, aldehydes, and pteridines. Some artificial dyes such as methylene blue are able to accept elections from the iron sulfur centers (Salaris et al, 1991). X O and X D H differ from each other primarily at the F A D site, where X O donates electrons solely to molecular oxygen and X D H preferentially donates electrons to N A D + (Saito and Nishino, 1989). The probable pathways of election transfer are summarized