Karen Bedard and Karl-Heinz Krause

246 KAREN BEDARD AND KARL-HEINZ KRAUSE
processes. NOX deficiency may lead to immunosuppresion, lack of otoconogenesis, or hypothyroidism. Increased
NOX actvity also contributes to a large number or pathologies, in particular cardiovascular diseases and neurodegeneration.
This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology
and pathology.
I. INTRODUCTION
The NOX family NADPH oxidases are proteins that
transfer electrons across biological membranes. In general,
the electron acceptor is oxygen and the product of
the electron transfer reaction is superoxide. The biological
function of NOX enzymes is therefore the generation
of reactive oxygen species.
A. Reactive Oxygen Species
Reactive oxygen species (ROS) are oxygen-derived
small molecules, including oxygen radicals [superoxide
(O 2 � ), hydroxyl ( OH), peroxyl (RO2 ), and alkoxyl
(RO�)] and certain nonradicals that are either oxidizing
agents and/or are easily converted into radicals, such as
hypochlorous acid (HOCl), ozone (O 3), singlet oxygen
( 1 O 2), and hydrogen peroxide (H 2O 2). Nitrogen-containing
oxidants, such as nitric oxide, are called reactive nitrogen
species (RNS). ROS generation is generally a cascade of
reactions that starts with the production of superoxide.
Superoxide rapidly dismutates to hydrogen peroxide either
spontaneously, particularly at low pH or catalyzed by
superoxide dismutase. Other elements in the cascade of
ROS generation include the reaction of superoxide with
nitric oxide to form peroxynitrite, the peroxidase-catalyzed
formation of hypochlorous acid from hydrogen peroxide,
and the iron-catalyzed Fenton reaction leading to
the generation of hydroxyl radical (468, 874).
ROS avidly interact with a large number of molecules
including other small inorganic molecules as well as proteins,
lipids, carbohydrates, and nucleic acids. Through
such interactions, ROS may irreversibly destroy or alter
the function of the target molecule. Consequently, ROS
have been increasingly identified as major contributors to
damage in biological organisms. In 1956, Harmann made
his ground-breaking observations on the role of ROS in
the aging process (350), and the concept of ROS as agents
of cellular damage became widely accepted in theories of
aging (73). Yet, at least one beneficial function of ROS
production was also realized quite early, namely, the importance
of ROS in host defense. This point became particularly
clear when the link was made between deficiency
in ROS generation and reduced killing ability in
leukocytes. However, over the last decades, a second
important concept of ROS has been evolving. In fact, ROS
are involved not only in cellular damage and killing of
pathogens, but also in a large number of reversible regulatory
processes in virtually all cells and tissues. This
review discusses both the physiological and pathophysiological
role of ROS generated by the NADPH oxidase
family of enzymes.
B. Physiological Sources of ROS
Physiol Rev VOL 87 JANUARY 2007 www.prv.org
The physiological generation of ROS can occur as a
byproduct of other biological reactions. ROS generation
as a byproduct occurs with mitochondria, peroxisomes,
cytochrome P-450, and other cellular elements (50, 307,
314, 356, 588, 636, 715, 791, 874). However, the phagocyte
NADPH oxidase was the first identified example of a
system that generates ROS not as a byproduct, but rather
as the primary function of the enzyme system. The discovery
of other members of the NOX family of NADPH
oxidases demonstrated that enzymes with the primary
function of ROS generation are not limited to phagocytes.
In fact, the ROS-generating enzymes described in this
review are found in virtually every tissue. This review
focuses on novel homologs of the phagocyte NADPH
oxidase. A complete coverage of the biochemistry and
physiology of the phagocyte NADPH oxidase itself is beyond
the scope of this review. However, we give an
overview of the phagocyte NADPH oxidase to serve as a
framework to understand the specific features of novel
NOX isoforms (see sect. IIA1).
C. ROS-Generating NADPH Oxidase:
A Historical Overview
Although the NADPH oxidase was not yet identified,
a respiratory burst by cells had already been described by
the first half of the 20th century. These early observations
were done in sea urchin eggs (938), phagocytes in 1933
(51), and spermatocytes in 1943 (565). In 1959, Sbarra and
Karnovsky (787) demonstrated that the phagocyte respiratory
burst was an energy-requiring process that depended
on glucose metabolism. Shortly after, in 1961, Iyer
et al. (419) showed that the phagocyte respiratory burst
results in the generation of hydrogen peroxide. There was
a major controversy over whether the main substrate for
the enzyme system was NADPH or NADH. In 1964, Rossi
and Zatti (755) correctly proposed that an NADPH oxidase
was responsible for the respiratory burst. In 1970,
Klebanoff (466) demonstrated a contribution of myeloperoxidase
to the respiratory burst-dependent antimicrobial
activity of phagocytes. In 1973, Babior et al. (43) reported
that the initial product of the respiratory burst oxidase
was superoxide and not hydrogen peroxide.
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