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NOX enzymes as drug targets

K. Krause,David J. Lambeth,M. Krönke

Published 2012 in Cellular and Molecular Life Sciences

ABSTRACT

The Nox field (for review see [3, 4] has seen two distinct epochs: (1) the Age of the Phagocyte Oxidase, which began in earnest more than 30 years ago, during which the respiratory burst oxidase was believed to be the sole “professional” generator of reactive oxygen species (ROS), the production of which was thought to be largely confined to phagocytic cells, and (2) the Age of the Nox Family, which began around the turn of the 21st century and which showed the existence of multiple Nox isoenzymes. The Age of the Phagocyte Oxidase revealed that an NADPH-dependent, superoxide-generating respiratory burst oxidase is essential for microbial killing by phagocytes, elucidated the key catalytic (Nox2) and regulatory (p22phox, p47phox, p67phox, p40phox, Rac) subunits that control this enzyme, and showed that the genetic absence or mutation of individual NADPH oxidase components causes chronic granulomatous disease wherein affected individuals are prone to frequent, unusual infections. During the subsequent Age of the Nox Family, it was discovered that there are multiple Nox isoenzymes (seven in human—Nox1, Nox2, Nox3, Nox4, Nox5, Duox1, and Duox2—plus many more that are widely distributed among virtually all eukaryotic organisms from fungus to vertebrates), that they exist in a variety of cell types/tissues, and that they show varied mechanisms of activation. Mostly during the 1990s (prior to and leading up to the second Nox epoch) investigators in diverse fields had observed that superoxide or hydrogen peroxide was produced in their non-phagocyte tissue/cell de jour, often in response to a hormone or growth factor. Nevertheless, the phagocyte oxidase was usually absent, sometimes leading to the misidentification of the source of ROS as mitochondria or a side reaction by another enzyme. In addition, the 1990s gave rise to early clues that ROS might be important in the pathogenesis of disease states in a range of tissues. Thus, by the early 2000s, many clinically important fields were poised to make the most of the newly discovered Nox family. This has resulted in a decade of enormous cross-disciplinary excitement and growth, and has required those of us who grew up in the first Nox epoch to become fluent in a variety of new clinical “languages”.

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