Detoxification of Oxygen Free Radicals

Manganese is the cofactor for catalases, peroxidases and superoxide dismutases, which are all involved in the detoxification of reactive oxygen species (SOD). We consider here the widely distributed Mn SOD, and then briefly describe the dinuclear Mn catalases. 

1 We mentioned earlier that this family of bacteria has adapted to its environment to function without iron, using Co and Mn instead. 

FIGURE 16.3 (a,b) The water-splitting site as reported by Ferreira et al. (2004). (a) The MnaCa cluster positioned within the Mn- 

FIGURE 16.4 (a,b) Possible mechanisms for formation of dioxygen during the S4-S0 transition. (Adapted rom Barber, 2008.) 

FIGURE 16.5 The protein fold of Mn- orFe-SODs (left) and the active site (right). (From Miller, 2004. Copyright 2004 with permission from Elsevier.) 

The disproportionation of hydrogen peroxide is thermodynamically favourable however, rapid reaction requires a two-electron catalyst. For haem catalases, this is achieved by cycling between Fe and Fe porphyrin 

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Introduction Mn Chemistry and Biochemistry Photosynthetic Oxidation of Water — Oxygen Evolution Mn and Detoxification of Oxygen Free Radicals Nonredox di-Mn Enzymes — Arginase... 

Fig. 11 Biochemical pathways for the formation, detoxification, and cellular effects of xenobiotic free radical intermediates and reactive oxygen species (ROS). Fe iron, G-6-P glucose-6-phos-phate, GSH glutathione, GSSG glutathione disulfide, H2O2 hydrogen peroxide, FIO hydroxyl radical, LPO lipoxygenase, NADP nicotinamide adenine dinucleotide phosphate, O2 superoxide, P450 cytochromes P450, PHS prostaglandin H synthase, SOD superoxide dismutase. (Modified from Wells et al. 1997)...

Copper is part of several essential enzymes including tyrosinase (melanin production), dopamine beta-hydroxylase (catecholamine production), copper-zinc superoxide dismutase (free radical detoxification), and cytochrome oxidase and ceruloplasmin (iron conversion) (Aaseth and Norseth 1986). All terrestrial animals contain copper as a constituent of cytochrome c oxidase, monophenol oxidase, plasma monoamine oxidase, and copper protein complexes (Schroeder et al. 1966). Excess copper causes a variety of toxic effects, including altered permeability of cellular membranes. The primary target for free cupric ions in the cellular membranes are thiol groups that reduce cupric (Cu+2) to cuprous (Cu+1) upon simultaneous oxidation to disulfides in the membrane. Cuprous ions are reoxidized to Cu+2 in the presence of molecular oxygen molecular oxygen is thereby converted to the toxic superoxide radical O2, which induces lipoperoxidation (Aaseth and Norseth 1986). 

Our investigation revealed that enzymatic systems of oxygen radicals and lipoperoxides detoxification may play a leading role in the inhibition of free radical... 

DNA is also susceptible to free radical attack during oxidative stress. The participation of GST isoenzymes in the detoxification and repair of the potentially mutagenic radical damage to DNA has been studied by Ketterer and his colleagues. Both thymine hydroperoxides and DNA peroxidized by ionizing radiation in the presence of oxygen have been shown to serve as substrates for rat GST (T3, T4). However, these workers reported that the specificity of rat GST isoenzymes toward the peroxidized DNA differs from that toward the free thymine hydroperoxide, 5-hydroxymethyl uracil. From their data, Ketterer et al. (K7, K9) propose that GST act in concert with DNA glycosylase to repair oxidized DNA. 

Oxidative stress is broadly defined as a perturbation of cellular homeostasis, so that the production rate of reactive oxygen species (ROS) exceeds their neutralization rate. If homeostasis is not reestablished, oxidative stress may progress toward the onset of apoptotic cell death and tissue degeneration [103]. In order to cope with excessive production of free radicals, human bodies have developed sophisticated mechanisms for maintaining redox homeostasis. These protective mechanisms include ROS scavenging or detoxification, ROS production blockage, and... 

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