Xanthine dehydrogenase , electron

R is an electron-donor substrate such as purine or xanthine and A is an electron acceptor such as 02 or NAD+. It is thought that the in vivo mammalian form of xanthine oxidase uses NAD+ as acceptor and is therefore, more appropriately named xanthine dehydrogenase. No evidence exists for a dehydrogenase form of aldehyde oxidase. The specificities of xanthine oxidase and aldehyde oxidase have been extensively catalogued (96), and the mechanism and properties of these enzymes have been reviewed (97, 98). 

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. 

These enzymes catalyze the two-electron oxidation of purines, aldehydes and pyrimidines, sulfite, formate and nicotinic acid in the general reaction shown in equation (49). These enzymes show some differences in properties. Xanthine oxidase, xanthine dehydrogenase and aldehyde oxidase all have relatively low redox potentials and a unique cyanolyzable sulfur atom, and so will be discussed together. 

Xanthine oxidase and xanthine dehydrogenase are two closely related enzymes which differ in the nature of their terminal electron acceptor, the oxidase using 02 and the dehydrogenase using... 

Any discussion of the mechanism of xanthine oxidase should attempt to incorporate the special features of xanthine oxidase (and xanthine dehydrogenase and aldehyde oxidase) which are not present, for example, in sulfite oxidase. There are two such features at least (a) the involvement of two protons rather than the one found for sulfite oxidase, and (b) the presence of the cyanolyzable sulfur atom. The mechanistic features discussed so far involve the abstraction of two electrons and a proton. This means that a carbonium ion is generated, which could undergo attack by a nucleophile. Thus, the presence of a nucleophile at the active site could lead to the formation of a covalent intermediate that will break down to give the products.1032 The nucleophile could either be the cyanolyzable sulfur atom or a group associated with the second proton. A possible scheme is shown in Figure 41. 

Molybdenum is a component of at least three enzymes aldehyde oxidase, xanthine dehydrogenase, and sulfite oxidase. The first two contain FAD, whereas the last is a heme protein similar to cytochrome c. Xanthine dehydrogenase can also act as an oxidase, that is, it can use 02 as an electron acceptor. Physiologically, however, it uses NAD+ as an electron acceptor when it converts hypoxanthine to xanthine and the latter to uric acid (see Chapter 10). Aldehyde and sulfite oxidases are true oxidases physiologically they both use 02 as an electron acceptor. Molybdenum in all three enzymes is associated with a pterinlike cofactor whose structure is shown in Figure 6.11. The Mo cofactor cannot be... 

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. 

ROS can be generated from multiple sources. These include mitochondrial electron transport, NOS activity, arachidonic acid metabolism, and xanthine oxidase (produced by hydrolysis of xanthine dehydrogenase). Moreover, altered binding of transition metals such as iron due to acidic conditions in ischemia may increase their participation in the Haber-Weiss reaction (Halliwell, 1992). In addition, P450 enzyme.s and NAD (P)H oxidase are possible sources of ROS. 

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