ROS as Signalling Molecules

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Scientists have long had evidence that ROS and other free radicals are toxic substances that are the cause of diseases and aging (Stadtman, et al., 2008). This led, perhaps inescapably, to the idea that ROS are solely harmful to the cell, the "bad guys" if you will, and antioxidants which serve to limit their destruction as the "good guys". However, recent discoveries have shown evidence that ROS could also act as signalling molecules (Hancock, Desikan, & Neill, 2001) and their production within the cell is necessary in its normal physiological function. In order to act as a signalling molecule, target specificity is needed. However, ROS is well known for its damaging effects; specificity is the last thing in mind when ROS is considered. To resolve this apparent contradiction, the biochemistry of ROS must be reconsidered.

ROS Biochemistry

The ROS family consist of three different types of molecules, namely superoxide (•O2-), hydrogen peroxide (H2O2), and the hydroxyl radical (•OH). These are generally produced by electron transfer reactions, which can be accidentally or deliberately mediated by enzymatic or nonenzymatic reactions. Due to electron spin restrictions, oxygen is commonly reduced by adding electrons one at a time. Thus, the reduction of O2 to 2H2O requires four electrons, and the univalent pathway involves free radical intermediates which are much more reactive than O2 itself. It is these intermediates of oxygen reduction that are commonly termed as reactive oxygen species (ROS).

O2+ e- →O2-

O2- +e-+2H+ → H2O2

H2O2 + e- +H+→ H2O + HO•

HO∙ + e- + H+→ H2O

Free radicals are chemical species capable of independent existence that possesses one or more unpaired electrons in the valence shell of their molecule. They can be formed by the loss of a single electron from a stable molecule, or by the gain of an electron to a molecule. The radicals can also be formed when a covalent bond is broken if one electron from each of the pair shared remains with each atom, a process known as homolytic fission. The energy required to dissociate the covalent bond can be provided by ultra-violet light, heat or ionizing radiation among others.

2.1.1. Types and sources of free radicals

In biological systems, free radicals are generally produced by electron transfer reactions, which can be accidentally or deliberately mediated by enzymatic or nonenzymatic reactions. The most biologically significant free radicals are the radical derivatives of oxygen better known as ROS (Cheeseman and Slater, 1993). These include superoxide (•O2-), hydroxyl radical (•OH), nitric oxide (NO•), peroxynitrite (ONOO-), and hypochlorous acid (HOCl).

The superoxide anion created from molecular oxygen by the addition of an electron is, in spite of being a free radical, not highly reactive (Faraggi & Houee-Levin, 1999). Most of its reactions are as a one-electron oxidant or one-electron reductant. However, the radical is produced in significant amounts intracellularly, both in the mitochondria, mainly due to the electron leakage from the respiratory chain and in cytosol via flavoenzymes, such as xanthine oxidase (Kuppusamy and Zweier, 1989) activated in ischemia-reperfusion (Zimmerman and Granger, 1994). Other superoxide-producing enzymes are lipoxygenase, cyclooxygenase and NADPH oxidase (Kontos et al., 1985; McIntyre et al., 1999). peroxide

Hydrogen peroxide generated from the two electron reduction of oxygen is not a free radical but an oxidizing agent that is not particularly reactive. In cells, two superoxide molecules can react together to form hydrogen peroxide and oxygen. This is a dismutation reaction as the radical reactants produce nonradical products.

Dismutation Reaction

SOD---M(n+1)+ + O2− → SOD---Mn+ + O2

SOD---Mn+ + O2− + 2H+ → SOD---M(n+1)+ + H2O2

where M = Cu (n=1) ; Mn (n=2) ; Fe (n=2) ; Ni (n=2).

However, interest in the physiological role of this simple diatomic molecule has risen exponentially in the 12 years since the endothelium-derived relaxing factor (EDRF), first proposed by Furchgott and Zawadski in 1980, (Furchgott & Zawadzki, 1980) was identified in 1987 by Palmer et al (Palmer, Ferrige, & Moncada, 1987) as NO. In 1992, interest was such that NO was voted "molecule of the year" by Science and earned Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad the Nobel Prize in Physiology or Medicine in 1998 for their discoveries concerning "nitric oxide as a signalling molecule in the cardiovascular system."




• Agonist or stimulus-coupled

• May or may not be agonist or stimulus-coupled

• Driven by exogenous agents or substances produced at pathophysiological levels

•Compartmentalized (spatiotemporally restricted)

• Often compartmentalized, but not a requirement

• Generally not compartmentalized

• Coordinately regulated at multiple steps of the transduction pathways (multiple targets)

• May be targeted precisely, often to one protein that acts as the sensor and/or transducer of a response

• Spatiotemporally promiscuous

• Targeted precisely (highly substrate specific)

• Dynamic and reversible

• Often reversible, though not a necessary requirement

• Often irreversible

• Operates on physiological time scales, usually milliseconds to minutes

• Operates on lengthy time scales, usually hours to days

• Timescale may range from acute to chronic depending on level of insult




Regulation of trafficking of AMPA receptors, epidermal growth factor receptors and adrenergic receptors by S-nitrosylation (7, 8)

Bacterial response to nitrosative and oxidative stresses by S-nitrosylation and S-oxidation of OxyR, a prokaryotic transcription factor (13, 14)

Neurodegeneration promoted by S-nitrosylation of protein disulfide isomerase (18) and Parkin, a ubiquitin-ligase (19), or by Tyr nitration of synuclein (20)

Regulation of endothelial cell (9) and platelet granule exocytosis (10), and insulin secretion (11) by S-nitrosylation

Anchorage and growth of transformed cells by ROS-dependent Src oxidation (15)

Dysregulation of skeletal muscle Ca2+ signaling by Tyr nitration and thiol oxidation of the sarcoplasmic reticulum Ca2+ ATPase (21)

Regulation of ventilatory drive (12) by S-nitrosylation-based signaling

S-oxidation and S-nitrosylation of Tyr phosphatases by growth factor (16) and stress signals (17)

Increases in Tyr nitration in ARDS (22) and other inflammatory disorders (23)

Table 1. The many effects of ROS on the cell (Forrester & Stamler, 2007).