Copper metabolism regulation

In mammals, as in yeast, several different metallothionein isoforms are known, each with a particular tissue distribution (Vasak and Hasler, 2000). Their synthesis is regulated at the level of transcription not only by copper (as well as the other divalent metal ions cadmium, mercury and zinc) but also by hormones, notably steroid hormones, that affect cellular differentiation. Intracellular copper accumulates in metallothionein in copper overload diseases, such as Wilson s disease, forming two distinct molecular forms one with 12 Cu(I) equivalents bound, in which all 20 thiolate ligands of the protein participate in metal binding the other with eight Cu(I)/ metallothionein a molecules, with between 12-14 cysteines involved in Cu(I) coordination (Pountney et ah, 1994). Although the role of specific metallothionein isoforms in zinc homeostasis and apoptosis is established, its primary function in copper metabolism remains enigmatic (Vasak and Hasler, 2000). 

Another common biomarker for trace metal exposure is the metal-binding protein metallothionein, which regulates normal zinc and copper metabolism and provides a mechanism for metal detoxification. Changes in metallothionein activity provide a sensitive marker of trace metal exposure. 

Four major MT isoforms, MT-1, MT-2, MT-3, and MT-4, have been identified in mammals. The most widely expressed isoforms in mammals, MT-1 and MT-2, are rapidly induced in the liver by a wide range of metals, drugs, and inflammatory mediators. In the gut and pancreas, MT responds mainly to Zn status. A brain isoform, MT-3, has a specific neuronal growth inhibitory activity, while MT-1 and MT-2 have more diverse functions related to their thiolate cluster structure. These include involvement in Zn homeostasis, protection against heavy metal (especially Cd) and oxidant damage, and metabolic regulation via Zn donation, sequestration, and/or redox control. A possible role for MT-4 is related to copper requirements in epithelial differentiating tissues. 

Harris BO, Qian Y, Reddy MC. Genes regulating copper metabolism. Mol Cell Biochem 1998 Nov 188(l-2) 57-62. 

Ceruloplasmin (Cp), secreted into the blood stream, appears to be ubiquitous in vertebrates. There is extensive in vitro evidence that Cp efficiently catalyzes the oxidation of Fe to Fe under near physiological conditions. The role of Cp in iron metabolism is widely accepted and there is strong evidence for a secondary role in copper transport/regulation. Defects in hepatic biosynthesis of Cp may result in diseases such as Wilson s disease. There is conclusive evidence that Cp is the source for the copper found in cytochrome c oxidase and CuZn-SOD in cells. Cp inhibition of Fenton chemistry-induced oxidative damage of deoxyribose, lipids, and DNA points to an antioxidant role, which would explain the increase in Cp concentration in response to acute infection or inflammation. 

Other d-metals are also vital to health. For example, chromium(III) plays a role in the regulation of glucose metabolism. Copper(I) is an essential nutrient for healthy cells and is the only biologically available Lewis acid with a + 1 charge. 

The exact cause of Alzheimer s disease remains unknown, although a number of factors have been suggested. These include metabolism and regulation of amyloid precursor protein, plaque-related proteins, tau proteins, zinc, copper, and aluminum [1]. 

Minerals include sodium, potassium, calcium, phosphorus, magnesium, manganese, sulphur, cobalt and chlorine trace minerals include iron, zinc, copper, selenium, iodine, fluorine and chromium. Their roles may be generalised within the areas of providing structure in the formation of bones and teeth, maintenance of normal heart rhythm, muscle contractility, neural conductivity, acid-base balance and the regulation of cellular metabolism through their activ-ity/structural associations with enzymes and hormones. The daily requirements of minerals can be obtained from a well-balanced diet. 

In this article, we will focus mainly on the mechanisms of iron and zinc regulation, because regulation of these two metals illustrates many basic principles. We will also reference reviews that address regulation of copper and manganese metabolism, but regulation of these metals will not be discussed in depth here, in part because they will be discussed elsewhere. 

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. 

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