Reactive oxygen species generation at the plasma membrane for antibody control
Introduction
The oxidation of antibodies depends on the availability of oxidants outside of cells [1]. Oxidants circulating in the serum will be available for oxidation in all tissues whereas oxidants produced selectively in individual tissues will favor oxidation at the source tissue. The most prevalent oxidants produced by cells are reactive oxygen species (ROS). These include superoxide, hydrogen peroxide and peroxynitrite. In special situations superoxide or peroxide generation can be based on cytosolic proteins such as xanthine oxidase, monoamine oxidase, cyclooxygenase, lipoxygenase, of disulfide bond formation. More general sources of ROS are membrane based redox systems located in mitochondria, plasma membrane, golgi or other endomembranes. ROS production by these membrane redox systems can be cell or tissue specific which means that ROS generation can be localized for antibody oxidation [2].
Section snippets
Mitochondrial oxidant generation
The high respiratory activity in mitochondria has often been considered as a primary basis for H2O2 generation in cells [3]. However the rate of H2O2 production by healthy mitochondria is very low so the extent to which it contributes to normal H2O2 production has been questioned [4]. Agents or conditions which inhibit mitochondria electron transport to increase the ratio of ubiquinol to ubiquinone, with increase in semiquinone, will increase superoxide formation and subsequently hydrogen
The NOX family of NADPH oxidases
The NOX family of NADPH oxidases provides a tissue specific and well controlled source of extracellular superoxide or hydrogen peroxide. Seven members of the group have been characterized and identified in various cells and tissues (Table 1). They include NOX 1–5, and DuoNOX 1 and 2 [7]. All of the NOX oxidases have as the primary catalytic element homologues of the transmembrane protein GP91 phox which was first identified as the oxidase responsible for superoxide and peroxide generation in
NADH oxidase
The plasma membrane of many cells also contains a transmembrane NADH oxidase which can generate superoxide and hydrogen peroxide outside the cell [13]. This enzyme complex is subject to different controls and involves different redox carriers than the NADPH (NOX) oxidases [14]. The primary control on ROS generation by the NADH oxidase is the concentration of NADH in the cytoplasm. When lactate is supplied to increase cytosolic NADH the plasma membrane oxidase generates more superoxide [15]. If
Conclusion
The evidence for oxidant control of antibody action [1], [18] brings up an entirely new area of influence for the oxidant generating plasma membrane oxidases. The selective activation of these oxidases in various cells provides specificity of antibody activation or masking which may represent a response to stress of various types (physical or mental) or the presence of agents in the serum which control the oxidases. The mode of action by the ROS produced may range from protein sulfhydryl
Take-home messages
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Oxidative modification of antibodies can be based on oxygen radical generation by specialized enzymes at the cell surface.
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These enzymes include NADPH and NADH oxidases with different expression in different tissues.
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They are selectively activated by hormones and cytokines to produce superoxide, peroxide and peroxynitrite leading to modification of functional groups on antibodies.
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Radical generation by the plasma membrane enzymes would be in addition to any radical generation by mitochondria and
Acknowledgement
We appreciate the assistance of Ms. Melanie Davis in preparation of the manuscript.
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