Xanthine Oxidoreductase An Enigmatic Enzyme

Considerable research has been focused on XOR and its role in health and disease. Yet the extent of XOR involvement in disease processes has been debated over several decades. Questions remain concerning the low level of XOR activity in human tissues and about the exact significance of the conversion of XOR from the dehydrogenase to the oxidase form. However, there is no doubt that the enzyme can generate ROS and can be upregulated under a variety of pathological stimuli. Low basal XOR activity in normal human endothelial cells probably represents a tighter regulation in human versus other species. The debate regarding the significance of the conversion from the dehydrogenase to the oxidase form may be somewhat irrelevant since both forms of the enzyme can produce ROS. Therefore, as long as overall activity is upregulated under specific conditions, it is likely that ROS will be produced either as signaling molecules or as injurious agents depending on the situation.

The fact that uric acid, the end product of XOR catalysis in humans, is a strong antioxidant also raised speculation about the importance of XOR catalysis as an antioxidant rather than a pro-oxidant system. However, XOR continues to be a formidable generator of ROS when exogenously added to cultured cells. In vivo, XOR-derived ROS may be sufficient to directly damage cells, or to combine with NO (in the case of superoxide) in endothelial cells to produce highly reactive and damaging species such as peroxynitrite. Alternatively, XOR-derived ROS may be operative as signaling molecules mediating specific cellular responses to stress, such as interaction of phagocytes with endothelial cells.

A recent review suggested an evolutionarily conserved role for XOR in innate immunity [3]. Microvascular endothelial cells or mammary and intestinal epithelial cells are proposed to protect the organism through production of the antioxidant uric acid. Furthermore, signaling through XO-derived ROS may help recruit phagocytes or directly neutralize pathogens when ROS are produced in large amounts. This view is consistent with a role for XOR in the inflammatory or acute-phase response in which the endothelial cell might be a major protagonist. By analogy to the inflammatory process, such a protective role for XOR is not incompatible with the notion that XOR might also cause damage in disease processes. An inflammatory reaction generally offers protection to the organism but can lead to deleterious effects when unregulated, and diseases ranging from asthma to coronary artery disease involve dysregulated immune responses. Likewise, the role of XOR in disease should be viewed in terms of dysregulation leading to signaling processes that alter endothelial cell physiology and/or interaction with other cells. Rather than focusing on XOR as a simple producer of oxidants or antioxidants, future studies need to explore new avenues and search, for example, for proteins that interact with the enzyme, or identify mechanisms that regulate the enzyme or target it to specific cell compartments. The horizon for XOR research, whether or not the enzyme, like Janus, offers two faces and remains very promising.

References

1. Garattini, E., Mendel, R., Romao, M. J., Wright, R., and Terao, M. (2003). Mammalian molybdo-flavoenzymes, an expanding family of proteins: Structure, genetics, regulation, function and pathophysiology. Biochem. J. 372, 15-32. A comprehensive review of the family of molybdo-flavoenzymes to which XOR belongs. It provides insights into its function and relationship to other enzymes such as aldehyde oxidase whose function is not well understood.

2. Harrison, R. (2002). Structure and function of xanthine oxidoreductase: Where are we now? Free Radic. Biol. Med. 33, 774-797. A comprehensive review of XOR that covers different aspects of its biochemistry and physiology. A very useful source for primary references on XOR research.

3. Vorbach, C., Harrison, R., and Capecchi, M. R. (2003). Xanthine oxi-doreductase is central to the evolution and function of the innate immune system. Trends Immunol. 24, 512-517. A discussion of the importance of XOR as a component of the immune system.

4. Enroth, C., Eger, B. T., Okamoto, K., Nishino, T., and Pai, E. F. (2000). Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: Structure-based mechanism of conversion. Proc. Natl. Acad. Sci. USA 97, 10723-10728. A description of the crystal structure of xanthine oxidase that relates biochemical behavior of the different forms of XOR to structural components of the protein.

5. Hassoun, P. M., Yu, F. S., Shedd, A. L., Zulueta, J. J., Thannickal, V. J., Lanzillo, J. J., and Fanburg, B. L. (1994). Regulation of endothelial cell xanthine dehydrogenase xanthine oxidase gene expression by oxygen tension. Am. J. Physiol. 266, L163-L171.

6. Kayyali, U. S., Donaldson, C., Huang, H., Abdelnour, R., and Hassoun, P. M. (2001). Phosphorylation of xanthine dehydrogenase/oxidase in hypoxia. J. Biol. Chem. 276, 14359-14365.

7. Page, S., Powell, D., Benboubetra, M., Stevens, C. R., Blake, D. R., Selase, F., Wolstenholme, A. J., and Harrison, R. (1998). Xanthine oxi-doreductase in human mammary epithelial cells: Activation in response to inflammatory cytokines. Biochim. Biophys. Acta 1381, 191-202.

8. Pfeffer, K. D., Huecksteadt, T. P., and Hoidal, J. R. (1994). Xanthine dehydrogenase and xanthine oxidase activity and gene expression in renal epithelial cells. Cytokine and steroid regulation. J. Immunol. 153, 1789-1797.

9. Granger, D. N., Hollwarth, M. E., and Parks, D. A. (1986). Ischemia-reperfusion injury: Role of oxygen-derived free radicals. Acta Physiol. Scand. Suppl. 548, 47-63.

10. McCord, J. M. (1985). Oxygen-derived free radicals in postischemic tissue injury. N. Engl. J. Med. 312, 159-163.

Capsule Biography

Usamah S. Kayyali, Ph.D., M.P.H., is Assistant Professor of Medicine at Tufts-New England Medical Center/Tufts University School of Medi cine. Dr. Kayyali's research interests include mechanisms of endothelial cell injury and signaling in hypoxia. His research focuses on p38 MAP kinase pathway, reactive oxygen signaling, and cytoskeletal regulation of endothelial physiology.

Paul M. Hassoun, M.D., is Associate Professor in the Department of Medicine at Johns Hopkins University School of Medicine, Division of Pulmonary and Critical Care Medicine. He is Director of the Pulmonary

Hypertension Program at Johns Hopkins Hospital. Dr. Hassoun has had a long-standing interest in pulmonary vascular diseases, endothelial biology, and the role of oxidant systems in vascular diseases. His research work is focused on the regulation of certain endothelial enzymes, such as xanthine oxidoreductase and nitric oxide synthase, and their functions in disease processes.

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