Metallothionein copper

Metallothioneins play an important role in the metabolism of copper, both in absorption and handling by the liver. Dietary supplementation with copper leads to a large increase in liver copper-metallothionein. The biological life of metallothionein can vary considerably. The half-life of Cu-metallothionein in zinc-deficient rats (12.3 h) was lower than that in zinc-sufficient rats (16.9 h).1166 Usually zinc is found in Cu-metallothionein, so zinc may stabilize the copper metallothionein.1167... 

Munger, K. Lerch, K. (1985). Copper metallothionein from the fungus Agaricus bisporus chemical and spectroscopic properties. Biochemistry 24, 6751-6. 

The mechanism by which MTF-1 facilitates zinc-induction of metallothionein promoter through the MREs is not known, but several models have been proposed. First, zinc may act as a coinducer by binding to MTF-1 and creating an allosteric change, allowing MTF-1 to bind to the MREs. The model proposed for mammalian MTF-l/MRE interaction has already been proven for yeast copper metallothionein systems (Furst et al., 1988). Another possibility may be that, under normal conditions, an inhibitor binds MTF-1. When an influx of zinc occurs, MTF-1 binds the zinc, undergoes a conformational change and is released from the inhibitor. The protein would then have the ability to bind to the MREs. Finally, upon an increase in intracellular zinc concentration, a specific coactivator may bind zinc and interact with MTF-1 to maximally induce transcription. 

The metal-binding proteins metallothionein and ceruloplasmin are recurring themes in the study of zinc and copper Metallothionein is a small protein with a protein binds zinc and copper ions, as well as nonnutritive heavy metals. The protein consists of about 60 amino acids, and has a molecular wreight of about 7000. One third of these amino acids (20 of them) are cysteine. The 20 sulfhydryl groups of these cysteine residues can bind a total of 7 bivalent metal ions, i.e., 7 zinc atoms or 7 copper atoms (l agi and Schaffer, 1988). 

It has been known for some time that Wilson s Disease in inherited as an autosomal recessive trait and that its prevalence in the general population amounts to one in 200,000 ( 82,89,90). The cause for the ceruloplasmin deficiency seems to be attributable to impairment of the lysosomal ability to excrete copper into bile, which is the major excretory route for copper (80,81). Bile pigments are known to be good copper chelators (91). In addition, a copper metallothionein with high binding capacity for copper has been identified in livers of subjects with Wilson s Disease (92) and in human fetal liver (93). 

With few exceptions, metallothioneins consist of relatively simple amino acids, aromatic amino acids and histidine only being found in a small number of species [329]. This amino acid composition suggests that metallothioneins evolved early in the evolution of life, probably even before the oxygenation of the atmosphere. A further clue is one of their functions. As metal-transport and storage proteins, thioneins are capable of binding metal ions but release them relatively easily as well. Metallothioneins can therefore be considered a transition from non-metal to metalloproteins. It is improbable, however, that the known copper proteins evolved from copper metallothioneins as there are no homologies between them and other copper proteins or enzymes. 

Patents have issued for the use of amino-acid complexes [253], copper-metallothioneins [254], compositions of copper compounds mixed with fatty acids [253], copper complexes of D-penicillamine, alkylcysteines [256, 257] and copper complexes offatty acids alone or mixed with metallic copper [258]. Compositions of copper compounds mixed with fatty acids were also claimed to be useful in the treatment of other inflammatory disorders, including cardiovascular and thrombotic disorders, menstrual cycle disorders, diabetes, endometriosis, nutritional deficiencies and malignancies [255]. Scheinberg has also obtained a Food and Drug Administration approved Investigational New Drug application for the treatment of RA with the mixed-valence copper penicillamine complex (personal communication). Preparations of Cu(II)-(oleate) are currently being sold in Europe for topical treatment of RA and other inflammatory disorders under the trade names of Kupfer and Kupfer Forte, which contains fine particles of metallic copper [258]. 

Belteamini M and Leech K (1982) Copper transfer between Neurospora copper metallothionein and type 3 copper apoproteins, FEBS Lett 142 219-222. 

The only reported structure for a copper metallothionein, also unique for an Ag-substituted derivative, is for yeast S. cerevisae), which includes 12 Cys and 1 His out of the 53 amino acid residues. The NMR solution structure of both forms allowed determination of the backbone fold for the first 40 residues of the protein. In addition, based on the fact that only seven major Ag resonances were observed for the reconstituted protein, the Ag-to-Cys connectivities were derived and assumed identical for Cu-MT. Overall, it was concluded that yeast binds seven Cu or Ag ions in a single cluster, using 10 out of the 12 available Cys residues.A recent NMR reinvestigation of CU7-MT from the same species has shown that a number of different arrangements of the seven copper ions is consistent with the highly refined structure of the polypeptide fold. This, together with the different coordination preferences of Cu and Ag with thiolate sulfur ligands (see below), casts doubt on the isostructurality of both metalloforms in yeast MT. ... 

The basic defect in this disease appears to be in the interaction of copper with the carrier protein caeruloplasmin to which it normally binds strongly. In many of the victims caeruloplasmin levels are low and an abnormally large amount of copper is weakly bound to serum albumin. However, some disease-free heterozygotes also have low levels of caeruloplasmin, while a minority of homozygotes have both normal caeruloplasmin levels and Wilson s Disease. The loss of copper in bile is often lower than normal and a metallothionein-like copper protein may be induced in the liver, perhaps causing the copper retention. An increased copper uptake firom the diet may also occur. Renal damage arises in the later stages of Wilson s disease, perhaps caused in part by the accumulation of a copper-metallothionein. 

Metal metabolism The use of zinc in the treatment of copper deposition due to Wilson s disease was first proposed in the Netherlands by Schouwink in his 1961 PhD thesis [107, 108 ]. This was based on earher experience in veterinary medicine in Australia that zinc salts are effective in copper poisoning in sheep. Later observations showed that stimulation by zinc of metallothionein blocks the intestinal absorption of copper. Metallothionein binds both zinc and copper, but it has a higher affinity for the latter. It binds newly absorbed copper in enterocytes and prevents it from passing firom the gut into the circulation. Copper has no enterohepatic circulation, and Ihe shedding of enterocytes with copper still bound to metallothionein results in higher fecal copper excretion. 

Placental metallothionein binds zinc and copper as well as cadmium. Zinc and copper are essential nutrients for the fetus whereas cadmium is toxic to the fetus and retained rather than transferred to the fetus. There is a question, therefore, as to how the essential metals are preferentially transported to the fetus while the toxic metal, cadmium, is retained. One possibility is that there is a greater sensitivity for zinc and copper metallothionein than cadmium metallothionein to the action of proteolytic enzymes present in trophoblasts. Degradation of the zinc and copper metallothionein complex facilitates the release of these metals to fetal blood, whereas cadmium metallothionein is resistant to this effect. 

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