Xanthine oxidase electron acceptor specificities

Krenitsky, T.A. Tuttle, J.V. Cattan, E.L. and Wang, P. A comparison of the distribution and the electron acceptor specificities of xanthine oxidase and aldehyde oxidase. Comp Biochem Physiol 49B 687-703, 1974. 

A comparison of xanthine oxidase and aldehyde oxidase was suggested by their functional and structural similarities. Both enzymes catalyze hydroxylation reactions in which water is the source of the hydroxyl group [6,7], both have particle weights around 300,000 [8,9], and both contain FAD, molybdenum, and iron in their internal electron transport chains [7,9]. This report summarizes the results of a comparison of the distributions, substrate specificities and electron acceptor specificities of these two enzymes [10,11] and discusses the possible implications of the findings. 

Aldehyde oxidase in extracts of a wide variety of animal tissues did not usually use NAD" as an electron acceptor [11]. In contrast, with xanthine oxidase, NAD" was usually a relatively efficient electron acceptor. The various electron acceptor specificity patterns observed with xanthine oxidase using NAD", ferricyanide... 

To test the generality of this phenomenon, a variety of mammalian tissue extracts were incubated at 37°. In most cases, the result was a loss of the activity with NAD" and a slower loss or even increase in the activity with oxygen. This treatment, therefore, tended to convert extracts with a pattern II specificity to a pattern III specificity. The rate at which these changes occurred at 37° varied markedly from tissue to tissue. Other investigators have presented evidence indicating that changes in the electron acceptor specificity of xanthine oxidase are accompanied by some proteolysis and/or sulfhydryl modification [13,14],... 

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). 

Aldehyde oxidase catalyzes the oxidation of aldehydes to carboxylic acids by dioxygen, but also catalyzes the hydroxylation of pyrimidines. Despite its rather broad specificity for substrates, it may well be that aldehyde oxidase should be regarded primarily as a pyrimidine hydroxylase. Thus, xanthine oxidase and aldehyde oxidase catalyze the hydroxylation of purines and pyrimidines respectively. The oxygen incorporated into the product comes from water, not 02. The dioxygen serves as the electron acceptor and other oxidizing agents may be used. 

Activation of drugs to give toxic products is common. Apart from non-enzymatic activation (e.g., via autoxidation), activation by enzymatic one-electron oxidation or reduction frequently occurs. Several non-specific oxidases and reductases are encountered in mammalian tissues. Enzyme systems that have been studied in detail are peroxidases and microsomal oxidases and reductases. Xanthine oxidase also has received some attention. In many insta .ces the end products of the reaction are critically dependent upon the presence of oxygen in the system. This is because oxygen is an excellent electron acceptor, i.e., it can oxidize donor radicals, forming superoxide in the process. In this way a redox cycle is set up in which the xenobiotic substrate is recovered. The toxic effects of the xenobiotic often can be attributed to the oxidative stress arising from such a cycle. However, it seems that for some substrates, oxidative stress of this kind can be less damaging than anaerobic reduction. Anaerobic reduction can lead to formation of further reduced products with additional toxicity. 

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