Xanthine dehydrogenase , electron transfer

R. Hille and R.F. Anderson, Coupled electron/proton transfer in complex flavoproteins — solvent kinetic isotope effect studies of electron transfer in xanthine oxidase and trimethylamine dehydrogenase. J. Biol. Chem. 276, 31193-31201 (2001). 

The rationale for studies on flavin semiquinone metal interactions stems from the presence of flavin coenzymes which participate in electron transfer in a number of metalloflavoproteins. Iron-containing redox centers such as the heme and nonheme iron sulfur prosthetic groups (Fe2/S2, Fe+ZS, or the rubredoxin-type of iron center) constitute the more common type of metal donor-acceptor found in metalloflavoproteins, although molybdenum is encountered in the molybdenum hydroxylases (e.g. xanthine oxidase, aldehyde dehydrogenase). 

Pyridine nucleotide-dependent flavoenzyme catalyzed reactions are known for the external monooxygenase and the disulfide oxidoreductases However, no evidence for the direct participation of the flavin semiquinone as an intermediate in catalysis has been found in these systems. In contrast, flavin semiquinones are necessary intermediates in those pyridine nucleotide-dependent enzymes in which electron transfer from the flavin involves an obligate 1-electron acceptor such as a heme or an iron-sulfur center. Examples of such enzymes include NADPH-cytochrome P4S0 reductase, NADH-cytochrome bs reductase, ferredoxin — NADP reductase, adrenodoxin reductase as well as more complex enzymes such as the mitochondrial NADH dehydrogenase and xanthine dehydrogenase. 

The cytosolic enzyme xanthine dehydrogenase catalyses the oxidation of hypoxanthine and xanthine to uric acid. It is thought to be located predominantly in the liver, small intestine and capillary endothelium in man [9]. However, the distribution is different in other species. In healthy tissue, most of the enzyme is present as the D form , which transfers electrons to NAD+ ... 

Several important mammalian enzymes, such as sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase, require molybdenum as a cofactor. This organic component is a molybdopterin complex.Sulfite oxidase is probably the most important enzyme in relation to human health. This enzyme catalyzes the last step in the degradation of sulfur amino acids, oxidizing sulfite to sulfate and transferring electrons to cytochrome c. Xanthine dehydrogenase and aldehyde oxidase hydroxylate a number of heterocyclic substances, such as purines, pteridines, and others. ... 

Mammalian XO is a homodimer of around 1330 amino acids which binds a number of electron transfer centres — an FAD, two spectroscopically distinct [2Fe-2S] clusters, and the Mo-cofactor. The structure of the bovine xanthine dehydrogenase (XDH), bound to the competitive inhibitor salicylic acid, and presented in Figure 17.3(a), consists of four domains, two Fe/S domains (1 and 11) in the N-terminal portion of the molecule, followed by the central FAD domain and the molybdenum-binding domain in the C-terminal part of the molecule. 

As with FMO, this enzyme has some inherent instability and care should be exercised in processing tissue samples of the presence of this enzyme is an issue. Aldehyde oxidase is a true oxidase, in that it transfers electrons to O2 (to form H2O2). The literature contains numerous reports about (milk) xanthine oxidase subsequent work revealed that this is really xanthine dehydrogenase (Rajagopalan, 1997), which is readily converted to an oxidase by proteolysis or modification of sulfides. 

Xanthine dehydrogenase, which is similar to xanthine oxidase, can accept six electrons on reduction. Electron transfer from the substrates xanthine and NADH is triphasic with initial rapid two-electron transfer to Mo followed by slower two-electron reduction of the flavin and subsequent one-electron addition to each of a pair of Fe4S4 centres. The latter two processes have rate... 

Ischaemia causes sustained elevation of free intracellular calcium ion concentration ([Ca ji), that can promote the conversion of xanthine dehydrogenase (EC 1.1.1.204) to xanthine oxidase (EC 1.1.3.22), i.e. the enzyme transfers electrons during the catalytic cycle of molecular oxygen instead of adenin-nicotin dinucleotides (McCord 1985). Under low energy conditions, where large parts of... 

---