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REVIEWS
NOX ENZYMES AND THE BIOLOGY
OF REACTIVE OXYGEN
J. David Lambeth
Professional phagocytes generate high levels of reactive oxygen species (ROS) using a superoxide-generating NADPH oxidase as part of their armoury of microbicidal mechanisms. The multicomponent phagocyte oxidase (Phox), which has been well characterized over the past three decades, includes the catalytic subunit gp91phox. Lower levels of ROS are seen in nonphagocytic cells, but are usually thought to be accidental byproducts of aerobic metabolism. The discovery of a family of superoxide-generating homologues of gp91phox has led to the concept that ROS are intentionally generated in these cells with distinctive cellular functions related to innate immunity, signal transduction and modification of the extracellular matrix.
SUPEROXIDE
The one-electron-reduced form of molecular oxygen.
PEROXIDASES
Haeme-containing enzymes that metabolize hydrogen peroxide with the concomitant oxidation of a co-substrate, such as chloride in the case of myeloperoxidase.
NADPH
The reduced form of nicotinamide adenine dinucleotide phosphate. This co-enzyme serves as an electron donor for various biochemical reactions.
Reactive oxygen species (ROS) include SUPEROXIDE,
hydrogen peroxide (H2O2), hydroxyl radicals and a variety of their reaction products (FIG 1 and BOX 1).
Probably because of the early discovery of enzymes such as superoxide dismutase (SOD)1, catalase and
PEROXIDASES that eliminate ROS from the cell, investigations over the past three decades have generally assumed that ROS are produced accidentally in cells, and that it was important for cells to eliminate these oxidizing species. This view was further reinforced by chemical studies that established that, under some conditions, superoxide and H2O2 react to generate hydroxyl radicals. These and other short-lived ROS react non-specifically and rapidly with biomolecules, including DNA, proteins, lipids and carbohydrates, and various investigations have elucidated roles for ROS in causing molecular damage such as DNA mutations, lipid peroxidation and protein oxidations. As a result of these investigations, ROS have historically been viewed as a harmful but unavoidable consequence of an aerobic lifestyle. For example, the mitochondrial respiratory chain, as well as many oxidative enzymes, generates small amounts of superoxide during normal function. The development of cardiomyopathy and neurodegeneration in knockout mice that lack Sod2 (the mitochondrial form of Sod)2 supports the idea that the generation of superoxide by mitochondria during normal metabolism is toxic to cells.
According to this view,...