Copper genetic mechanism

The underlying genetic mechanism of high copper tolerance to environmental copper in mammalian species was demonstrated in dogs which are free from copper toxicity in a high copper environment. 

The salt- and Cu2+-catalysed condensation of peptides provides a very simple polymerisation reaction with remarkable efficiency at 80°C. The proposed mechanism is shown in Figure 8.17 for the dimerisation of glycine. The presence of Cu2+ is important in this process and is unlikely to be present in the geothermal vent environment but it does require only small quantities of O2 to oxidise copper. A better condensation reaction would be autocatalytic and provide a template for future generations - in short, a genetic code. 

These solution NMR and X-ray crystallographic findings have been contradicted by X-ray structures solved by Rypniewski et al.32 The results show a reduced active site unchanged from the oxidized state and let these authors to propose a five-coordinate copper ion that exists throughout the oxidation and reduction process. In 2001 the Protein Data Bank listed 39 X-ray crystallographic and NMR solution structures for CuZnSOD, including oxidized, reduced, genetically modified, and other species with or without attached substrates or substrate mimics such as azide ion. The reader is advised to search the Protein Data Bank for additional and more up-to-date structural depositions and search the literature for further discussion of mechanism. 

Plant use of iron depends on the plant s ability to respond chemically to iron stress. This response causes the roots to release H+ and deduct ants, to reduce Fe3+, and to accumulate citrate, making iron available to the plant. Reduction sites are principally in the young lateral roots. Azide, arsenate, zinc, copper, and chelating agents may interfere with use of iron. Chemical reactions induced by iron stress affect nitrate reductase activity, use of iron from Fe3+ phosphate and Fe3+ chelate, and tolerance of plants to heavy metals. The iron stress-response mechanism is adaptive and genetically controlled, making it possible to tailor plants to grow under conditions of iron stress. 

Although genetic defects in the metahoUsm of trace elements are rare, they are nonetheless important because of the information they have provided as to homeostatic control mechanisms. This in turn has led to development of effective therapeutic strategies. The most commonly investigated disorders are those affecting iron (hemochromatosis), copper (Wilson s disease and Menkes syndrome), zinc (acrodermatitis enteropathica), and molybdenum (molybdenum cofactor disease). 

Genetic and nutritional studies have illustrated the essential nature of copper for normal brain function. Deficiency of copper during the foetal or neonatal period will have adverse effects both on the formation and the maintenance of myelin (Kuo et al., 2001 Lee et al., 2001 Sun et al., 2007 Takeda and Tamana, 2010). In addition, various brain lesions will occur in many brain regions, including the cerebral cortex, olfactory bulb, and corpus striamm. Vascular changes have also been observed. It is also of paramount importance that excessive amounts of copper do not occur in cells, due to redox mediated reactions such that its level within cells must be carefully controlled by regulated transport mechanisms. Copper serves as an essential cofactor for a variety of proteins involved in neurotransmitter synthesis, e.g. dopamine P-hydroxylase, which transforms dopamine to nor-adrenahne, as well as in neuroprotection via the Cu/Zn superoxide dismutase present in the cytosol. Excess free copper is however deleterious for cell metabolism, and therefore intracellular copper concentration is maintained at very low levels, perhaps as low as 10 M. Brain copper homeostasis is still not well understood. 

Menkes disease is a fatal genetic disorder with a widespread defect in copper transport. Most patients, when untreated, die by 3 years of age. The basic biochemical defect in Menkes patients is an inability to absorb copper through the intestine the inability to distribute copper to and within cells is also included in the mechanism of Menkes pathology. Treatment with copper histidine, Cu(His)2, is the only available treatment for Menkes disease. Interestingly, no other copper salts have been found to work. The mechanism of efficacy of Cu(His)2 is unclear. One hypothesis is the interplay between histidine and albumin in the transport of copper across membranes. 

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