The respiratory-burst enzyme

Because all aerobic cells generate 02 , which will dismutate (either spontaneously or enzymically) into H202, then, provided a suitable transition-metal salt is available for reaction (5.9), there is the possibility that OH formation may occur in biological systems. 

As we shall see later ( 5.4), there is some evidence that many, if not all of these reactive oxygen species are generated by phagocytosing neutrophils during the respiratory burst. The production of some of these is established beyond doubt, whereas the production of others, such as -OH, is controversial. 

The respiratory burst of phagocytes is catalysed by a membrane-bound NADPH oxidase that is responsible for the reaction  

The NADPH oxidase is in fact a multicomponent enzyme system that constitutes an electron transport chain from NADPH to O2. The components of this oxidase complex are now almost completely defined, and experiments performed primarily with CGD neutrophils have helped to identify these major constituents. 

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Bender, J. G., McPhail, L., C., van Epps, D. E. (1983). Exposure of human neutrophils to chemotactic factors potentiates activation of the respiratory burst enzyme. J. Immunol. 130,2316-23. 

CC, and one CX3C and XC chemokine receptors have been cloned so far [2]. Receptor binding initiates a cascade of intracellular events mediated by the receptor-associated heterotrimeric G-proteins. These G-protein subunits trigger various effector enzymes that lead to the activation not only of chemotaxis but also to a wide range of fimctions in different leukocytes such as an increase in the respiratory burst, degranulation, phagocytosis, and lipid mediator synthesis. 

Leukocytes are activated on exposure to bacteria and other stimuh NADPH oxidase plays a key role in the process of activation (the respiratory burst). Mutations in this enzyme and associated proteins cause chronic granulomatous disease. 

At the same time the interaction of superoxide with MPO may affect a total superoxide production by phagocytes. Thus, the superoxide adduct of MPO (Compound III) is probably quantitatively formed in PMA-stimulated human neutrophils [223]. Edwards and Swan [224] proposed that superoxide production regulate the respiratory burst of stimulated human neutrophils. It has also been suggested that the interaction of superoxide with HRP, MPO, and LPO resulted in the formation of Compound III by a two-step reaction [225]. Superoxide is able to react relatively rapidly with peroxidases and their catalytic intermediates. For example, the rate constant for reaction of superoxide with Fe(III)MPO is equal to 1.1-2.1 x 1061 mol 1 s 1 [226], and the rate constants for the reactions of Oi and HOO with HRP Compound I are equal to 1.6 x 106 and 2.2 x 1081 mol-1 s-1, respectively [227]. Thus, peroxidases may change their functions, from acting as prooxidant enzymes and the catalysts of free radical processes, and acquire antioxidant catalase properties as shown for HRP [228] and MPO [229]. In this case catalase activity depends on the two-electron oxidation of hydrogen peroxide by Compound I. 

Akard, L. P., English, D., Gabig, T. G. (1988). Rapid deactivation of NADPH oxidase in neutrophils continuous replacement by newly activated enzyme sustains the respiratory burst. Blood 72, 322-7. 

Nitric oxide and eicosanoid synthesis haem synthesis. The importance of the pentose phosphate pathway reduced glutathione in maintaining red cell integrity. The respiratory burst in phagocytes. Clotting and complement enzyme cascades. Metabolism of lipoproteins. 

Formation of the hydroxyl radical. Because the killing of certain microbes was dependent on the ability of PMNs to undergo the respiratory burst, the actual microbicidal species was sought. It had been shown that a potent oxidant was formed during the catalytic action of xanthine oxidase on xanthine an enzymic reaction which, like the PMN, produces both 07 and H2O2. This potent oxidant was proposed to be the hydroxyl radical formed by the reaction between O7 and H2O2 (reaction 4). Because such an oxidant seemed a likely candidate to mediate the microbicidal activity of PMNs, the formation of OH was assessed in PMNs. 

Some of the effects of products of the respiratory burst would appear to have opposing effects on the inflammatory response. Neutrophils stimulated with an antigen-antibody complex or by an enzymic source of Of inactivated the elastase-inhibitory activity in serum Inactivation was prevented by both catalase and... 

In the inherited syndrome of chronic granulomatous disease (CGD), cytochrome Z 245 is absent and consequently the respiratory burst cannot take place [6], Persistent, but selective, bacterial infections are seen in these patients. NADPH oxidase is useful as part of a controlled acute inflammatory response to bacterial invasion, but excessive activity of this enzyme might lead to tissue destruction. In addition to PMN s, other inflammatory cell types, e.g. lymphocytes and macrophages, possess a membrane NADPH oxidase [7], ROI production by these latter cell types may form part of an intercellular communication pathway important in the inflammatory response [8], and perhaps an absence of this cell signalling route in CGD patients is linked to the development of chronic granulomata in these patients. Interestingly, myeloperoxidase deficiency is not associated with disease. 

Superoxide is also a product of various enzyme reactions catalyzed by the flavin oxidases (e.g., xanthine oxidase and monoamine oxidase). In addition, 07 is a product of the noncatalytic oxidation of oxyhemoglobin, of which about 3% is converted each day to methemoglobin. Moreover, 02 is readily formed in phagocytic cells (i.e., neutrophils and monocytes) during the respiratory burst. Furthermore, in addition to the Fenton reaction, the Haber-Weiss reaction results in the conversion of 02 to the potent HO via the following reactions (H3) ... 

K17. Kobayashi, M., Tanaka, T., and Usui, T., Inactivation of lysosomal enzymes by the respiratory burst of polymorphonuclear leukocytes. Possible involvement of myeloperoxidase-H202-halide system. J. Lab. Clin. Med. 100, 896-907 (1982). 

The oxygen consumed during phagocytosis is utilized by a unique enzyme system termed the respiratory burst oxidase or NADPH oxidase. The oxidase generates superoxide anion (Oj), a one-electron reduced species, driven by intracellular NADPH,... 

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