Storage metallothioneins

As stated previously, the total normal cytoplasmic free copper concentration is less than 10 18 M or less than one copper ion per cell. In thermodynamic terms, almost all hydrated copper ions are immediately and tightly coordinated by amino acids or biopolymers—peptides, proteins, and other species with free sulfur ligands. An excess of copper ions activates metallothionein synthesis for storage or removal of the excess. Copper chaperones mediate transfer of copper ions from extracellular or storage locations to their target proteins. Instability of copper ion concentrations in vivo results in various disease states. Three of these—FALS, Menkes, and Wilson s diseases—are described below. 

When animals are fed experimental diets lacking copper or zinc, their copper or zinc status rapidly declines, suggesting that there is not a storage pool of these metals. Thus, while the small, cysteine-rich protein metallothionein (see below) can avidly bind zinc and copper, this may reflect its role in detoxification rather than as a specific storage form. This is reflected by the fact that metallothionein genes are typically expressed at a basal level, but their transcription is strongly induced by heavy metal load. 

Metallothioneins are an ubiquitous class of proteins with which the important roles of metal storage (Cu, Zn) and detoxification (Cd, Pb, Hg) are associated EXAFS studies have been carried out on a variety of metallothioneins including Zttj, ZUjCuj, ZiigCuj, Cd, and to show that metal atoms are exclusively... 

If zinc-containing domains lose their Zn2 they do not bind tightly to DNA. Regulation of the flow of zinc ions from storage sites in metallothioneins (Box 6-E) into transcription factors as well as into more than 300 enzymes poses interesting mechanistic questions.401... 

Whether specific storage forms are involved for the trace metals is debatable.107 Such a role has been alluded to for the non-exchangeable protein complexes in serum, i.e. caeruloplasmin for Cu, and a2-macroglobulin for Zn, and to metallothionein protein (Chapter 20.2). However, it has also been argued that there are sufficient deposits within body tissues to provide at least short-term storage of the minute quantities that are required. 

The addition of copper, zinc, cadmium or mercury to animals results in the synthesis of a cysteine-rich protein called metallothionein.1147-1149 These proteins have been isolated from a number of sources, and have molecular weights in the range 6000 to 12 000 with a cysteine content of about 30-35% of the total amino acid content. They have also been found in microorganisms and plants. These proteins are thought to play an important role in the storage of zinc and copper, and as a result of their storage capacity, are able to bind and detoxify cadmium and mercury. 

Metallothionein is a metal storage protein, not a circulating protein. Superoxide dismutases are present in various subcellular particles, for example mitochondria. Peroxisomes contain peroxidases such as catalase. Superoxide dismutases convert the superoxide anion to H202 and are absent from anaerobic microorganisms. 

Other proteins play important roles in controlling free metal concentrations in the cytosol. Of particular importance are ferritin and metallothionein. Ferritin is the major iron storage protein in the cell. It is critical that cytosolic iron is kept at low levels, because iron can catalize the Fenton reaction, which generates the most toxic of the ROS—the hydroxyl radical. Copper and superoxide can also participate in the fenton reaction. Metallothioneins are another important family of proteins that helps control cytosolic concentrations of metals such as Cu and Cd. Glutathione is another peptide that controls free Hg and Cd levels in the cell (Figure 21.7). 

The primary organs for copper storage are the liver and spleen, where the metal is found in the cytosol in superoxide dismutase see Copper Proteins with Type Sites) or metallothionein see Metallothiondns) In response to a copper challenge, yeast adaptively synthesizes metallothionein to detoxify the metal. Copper is also bound, transported, and assimilated into tissues by ceruloplasmin. 

Although metallothionein in liver binds zinc, there seems no apparent zinc storage in the body according to the kinetic analysis. ... 

These results together with published data [63,64] render the suggestion that copper and its storage protein — metallothionein — play similar roles in PC tempting. 

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