Oxidative stress iron homeostasis

Iron chelators can also be used to selectively bind iron in areas where oxidative stress is observed, thereby preventing the iron from taking part in Fenton reactions without interfering with normal iron homeostasis. Charkoudian et al. have developed boronic acid and boronic ester masked prochelators, which do not bind metals unless exposed to hydrogen peroxide (237,238). The binding of these chelators to iron(III) prevents redox cycling. Similar studies of these systems have been performed by a separate group (239,240). 

Fur is itself part of the family of gene regulatory proteins throughout many bacterial species. The major subclass is mainly involved, like Fur in E. coli, in the control of iron homeostasis, but it can also function in acid tolerance and protection against oxidative stress. Fur also controls the iron-regulated expression of bacterial virulence determinants. One class of the Fur family, Zur, is involved in the regulation of zinc uptake (see below). 

There is considerable evidence that defective homeostasis of redox-active metals, i.e. iron and copper, together with oxidative stress, contributes to the neuropathology of AD. The characteristic histology of AD is the deposition of both Ap, as neurotic plaques (Figure 18.12a), and of the protein tau, as neurofibrillary tangles NFT (Figure 18.12b), predominantly in the cerebral cortex and hippocampus. 

Meli R, Nauser T, Koppenol WH (1999) Direct observation of intermediates in the reaction of per-oxynitrite with carbon dioxide. Helv Chim Acta 82 722-725 Meneghini R (1997) Iron homeostasis, oxidative stress, and DNA damage. Free Rad Biol Med 23 783—... 

Iron comprises approximately 4.7% of the Earth s crust. The enormous quantities of this metal in the earth core are prerequisite for the magnetic field that shields the planet from cosmic radiation and enables life. The ubiquitous availability of iron and its ability to adjust its oxidation state, redox potential and electron spin state makes it suited to participate in a large number of chemical reactions. Thus, iron has become essential for animals, plants, fungi and most bacteria, ivhere it functions in a ivide variety of iron-dependent enzymes and metal proteins. To avoid deficiency symptoms, mechanisms have evolved in these organisms to maintain iron homeostasis in situations of scarce supply, but also to avoid oxidative stress as mediated by Fenton chemistry ivhen supply is excessive. In industry, iron is used in over 2500 varieties of steel, each with different physical properties. In fact, annual steel production is almost as high as that of all other metals combined hence the environmental effects of iron must also be considered. 

Heme is synthesized in mitochondria and plays a role in number of metabolic processes of the cell, controlling the activity of transcription factors, specific signaling pathways, cholesterol synthesis, and iron homeostasis. Heme can also convert less reactive oxidants to highly reactive free radicals, and disturbed heme metabolism can lead to mitochondria decay, oxidative stress, accumulation of iron, and cell death. 

Galaris D, Pantopoulos K (2008) Oxidative stress tmd iron homeostasis mechemistic and health aspects. Crit Rev CUn Lab Sci 45 1-23... 

An elucidation of the mechanisms of brain iron homeostasis, as outlined in figure 1, will help our understanding of AD especially since iron binds to Ap-peptide and enhances beta-amyloid toxicity [35-38]. Excess iron accumulation is a consistent observation in the AD brain. As discussed above, patients with hemochromatosis are at risk developing AD at an earlier age [2]. Brain autopsy samples from AD patients have elevated levels of ferritin iron, particularly in the neurons of the basal ganglia [39] and most amyloid plaques contain iron and ferritin-rich cells [40]. Clinically there is a reported decrease in the rate of decline in AD patients who were treated with the intramuscular iron chelator, desferrioxamine [41]. Iron enhances cleavage of the Ap-peptide domain of APP by the metalloprotease alpha secretase [42, 43]. Part of the protective effect of the major cleavage product of APP, APP(s), may derive from its capacity to scavange metals to diminish metal-catalyzed oxidative stress to neuronal cells [44]. APP is, itself, a metalloprotein [4]. 

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