| REACTIVE NITROGEN SPECIES (RNS)
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Nitric oxide synthases catalyze the production of the free radical, nitric oxide (NO•) from the amino acid l-arginine. NO•, known as the endothelium derived relaxation factor (EDRF), is an important signaling molecule with neurotransmitter activity. It has a role in the regulation of vascular tone (Chapter 17, p. 236), and is now thought to be an important regulator of the electron transport system. NO• competes with O2 for cytochrome c oxidase (complex IV), and decreases the membrane potential by inhibiting proton pumping and ATP production. At high levels of NO•, complex IV is strongly inhibited, and ROS production is increased.
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| Figure 35.3 Formation of ROS by the Fenton and Haber-Weiss reactions. (A) Fenton first described the oxidizing power of solutions of Fe2+ and H2O2. This reaction generates the strong oxidant OH•. Cu+ catalyzes the same reaction. (B) The Haber-Weiss reaction describes the production of OH• from O2• and H2O2. (C) Under physiological conditions, the Haber-Weiss reaction is catalyzed by redox-active metal ions. |
| Figure 35.4 Formation of superoxide by mitochondria. After the oxidation of NADH, the electron transport chain catalyzes single-electron redox reactions. The semiquinone radical, an intermediate in the reduction of Q to QH2 by Complex I or II, is sensitive to oxidation by molecular oxygen and is considered a major source of superoxide radicals in the cell. This reaction is enhanced at high oxygen tension and also at high membrane potentials, when the electron transport chain is saturated with electrons, e.g. at low oxygen tension during ischemia-reperfusion injury (see Box). |
| NO• reacts with O2• to form the strong oxidant, peroxynitrite (ONOO-), an RNS which has many of the strong
oxidizing properties of OH•, but has a longer biological half-life. ONOO- is a potent nitrating agent, and there is some evidence that ONOOH degrades, in part, by homolytic cleavage to produce two reactive species, OH• and NO2•. Simultaneous production of NO• and O2•, with the concomitant increase in ONOO- and a decrease in NO•, is thought to limit vasodilatation and cause inflammation of the vascular wall during ischemia-reperfusion injury, setting the stage for vascular disease. NO2•, another RNS with strong oxidizing and nitrating activity, is formed by eosinophil peroxidase or myeloperoxidase catalyzed oxidation of NO• by H2O2.
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| ROS and RNS induce oxidative, chemical (nonenzymatic) damage to biomolecules. Damage to proteins is often sitespecific, occurring at sites of metal binding to proteins, suggesting that metal-oxo complexes participate in ROS-mediated damage in vivo. As described later in this chapter, we have a range of antioxidant defenses against ROS, involving chelation of metal ions, enzymatic inactivation of ROS, trapping or degrading of ROS and intermediate reactive oxidation products by small molecules, vitamins and enzymes, and, in some cases, repair processes.
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