Superoxide in Biology and Medicine
Superoxide in Biology and Medicine
Superoxide in Biology and Medicine
Hopkins RZ. Reactive Oxygen Species 1(2):99–109, 2016; ©2016 Cell Med Press
http://dx.doi.org/10.20455/ros.2016.825
(Received: January 12, 2016; Revised: January 31, 2016; Accepted: February 1, 2016)
ABSTRACT | Since 1933 when Linus Pauling, a twice-honored Nobel laureate, proposed its existence based
on the theory of quantum mechanics, superoxide has gradually taken central stage in the research field of
reactive oxygen species (ROS) in biology and medicine. Indeed, superoxide is considered the primary ROS
that gives rise to secondary ROS. This oxygen free radical is generated in a wide variety of biological systems
ranging from aerobic microorganisms to human cells, and also formed in the deep ocean and the soils of Earth
and possibly the soils of Mars as well. Superoxide is now recognized as an important molecule that is formed
via defined mechanisms and involved in diverse physiological and pathophysiological processes. This article
provides an overview on the basic chemistry and biochemistry of this ubiquitous oxygen free radical and its
significance in biology and medicine.
KEYWORDS | Cytochrome P450 system; Fenton reaction; Haber-Weiss reaction; Mitochondria; NADPH
oxidase; Reactive oxygen species; Redox cycling; Redox signaling; Superoxide; Superoxide dismutase;
Uncoupled endothelial nitric oxide synthase; Xanthine oxidoreductase
ABBREVIATIONS | Cu,ZnSOD, Cu,Zn superoxide dismutase; CYP, cytochrome P450; ECSOD, extracellu-
lar superoxide dismutase; EPR, electron paramagnetic resonance; METC, mitochondrial electron transport
chain; MnSOD, manganese superoxide dismutase; NOX, NAD(P)H oxidase; ROS, reactive oxygen species;
SOD, superoxide dismutase; XO, xanthine oxidase
CONTENTS
1. Introduction
2. Sources of Superoxide
3. Chemistry and Biochemistry of Superoxide
3.1. Oxidation of Iron-Sulfur Clusters
3.2. Reaction with Nitric Oxide
3.3. Haber-Weiss Reaction and Fenton Reaction
3.4. Membrane Permeability and Protonation
4. Superoxide in Biology and Medicine
4.1. Phagocyte-Mediated Immunity
4.2. Redox Modulation and Signaling
1. INTRODUCTION
FIGURE 2. Major sources of cellular superoxide. NADPH oxidases (NOXs) and mitochondria are consid-
ered the major cellular sources of superoxide. Many other enzymes and cellular processes also contribute to
cellular superoxide production, such as xanthine oxidoreductase, cytochrome P450 (CYP) enzyme system (es-
pecially CYP2E1), and uncoupled endothelial nitric oxide synthase (eNOS).
presence in mitochondria, NOX4 is also found to un- implicated in a number of pathophysiological pro-
dergo translocation into the nucleus via a leukotriene cesses, such as atherosclerosis, inflammation, and
C4-dependent mechanism, and its presence in the tissue ischemia-reperfusion injury in the heart, liver,
nucleus contributes to oxidative damage to the nu- and kidneys [12].
clear DNA under stress conditions, including in- Cytochrome P450 (CYP) enzyme system, especial-
flammatory responses and treatment with cancer ly CYP2E1, is also a significant source of superoxide
chemotherapeutic agents [11] formation in cells, particularly under conditions
Notably, xanthine oxidoreductase has two inter- when these enzymes are induced by chemicals (e.g.,
convertible forms, namely, xanthine dehydrogenase ethanol). CYP2E1-derived superoxide/ROS upon
and xanthine oxidase (XO). Both forms catalyze the ethanol consumption may also be responsible for the
conversion of hypoxanthine to xanthine, and xan- upregulation of CYP2A5/2A6 by alcohol [13]. Re-
thine to uric acid. Both forms also catalyze one- and cently, a redox signaling heme-containing globin,
two-electron reduction of molecular oxygen to form namely, GLB-12, in Caenorhabditis elegans has
superoxide and hydrogen peroxide (H2O2), respec- been shown to generate superoxide, and the superox-
tively, with XO being more active in generating the ide produced may play a critical signaling role in
above ROS. The reversible conversion of xanthine regulating apoptosis and controlling the reproduction
dehydrogenase to XO occurs under certain condi- of the organism [14].
tions including hypoxia/tissue ischemia and oxida- In addition to the aforementioned endogenous
tion of the cysteine thiol groups of the enzyme. sources, superoxide is also formed during biotrans-
Xanthine oxidoreductase-derived ROS have been formation of certain xenobiotics, especially quinone
FIGURE 7. The cellular fate of mitochondria-derived superoxide. Mitochondrial electron transport chain
(METC) is the major source of cellular superoxide formation. The METC-derived superoxide undergoes
MnSOD-catalyzed dismutation to form H2O2, which is then converted to water by glutathione peroxidase
(GPx) or peroxiredoxin (Prx) in mitochondrial matrix. Superoxide is able to cross the mitochondrial inner
membrane and enter the cytosol, where Cu,ZnSOD catalyzes its dismutation to H2O2, and the H2O2 formed in
the cytosol or escaped from mitochondria is converted to water by enzymes, including GPx, Prx, and catalase
(CAT), in the cytoplasm. CuZnSOD present in the mitochondrial intermembrane space also catalyzes the dis-
mutation of superoxide present in the intermembrane space. ECSOD acts on extracellular superoxide.
and medicine. The coming years will likely witness 3. Fridovich I, Handler P. Xanthine oxidase. V.
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