Metallothionein protein synthesis

Elevated metallothionein levels are not necessarily indicative of heavy-metal insult. Starcher et al. (1980) show that liver metallothionein levels in mice are elevated following acute stress or starvation, and that this effect is blocked by actinomycin D, a protein synthesis inhibitor. It is further emphasized that not all zinc-binding proteins are metallothioneins (Webb etal. 1985 ... 

It is suggested that zinc is stored by metallothioneins in many tissues. These are low molecular weight proteins with a high incidence of cysteine residues. A zinc-binding protein, which is similar to metallothionein, has been isolated from yeasts477 and the cyanobacterium Anacystis nidulans478 Zinc uptake in energy-starved Candida utilis requires protein synthesis. While it is possible that... 

Metallothionein protein, found extensively in the brain, contains zinc, and so does cysteine-rich intestinal protein (cysteine is an amino acid). RNA proteins contain zinc as part of their structures. RNA, a protein, directs cellular protein synthesis using patterns taken from the DNA in the cell nucleus. 

Phytochelatin a plant peptide produced in response to lieavy metals, e.g. cadmium, copper, mercury, lead and zinc. The structure is (Y-Glu-Cys) -Gly (n = 3-7). Like Metallothionein (see), P. form metal-thiolate bonds and thus sequester toxic metal ions. They are probably derived from glutathione rather than RNA-directed protein synthesis. 

Halliwell B, Gutteridge JMC (1984) Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J 219 1-14 Hamer DH (1986) Metallothionein. Annu Rev Biochem 55 913-951 Hamet P (1992) Abnormal hsp70 gene expression its potential key role in metabolic defects in hypertension. Clin Exp Pharmacol Physiol [Suppl] 20 53-59 Hansen DK, Anson JF, Hinson WG, Pipkin JL Jr (1988) Phenytoin-induced stress protein synthesis in mouse embryonic tissue. Proc Soc Exp Biol Med 189 136-140... 

Matsubara J, Tajima Y, Karasawa M (1987) Promotion of radioresistance by metallothionein induction prior to irradiation. Environ Res 43 66-74 Miller L, Qureshi MA (1992) Heat-shock protein synthesis in chicken macrophages influence of in vivo and in vitro heat shock, lead acetate, and lipopolysaccharide. Poult Sci 71 988-998... 

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). 

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. 

Thioneins are apoproteins that are exceptionally sulfur-rich (composed of greater 30 mol% cysteine). These proteins are found in high abundance in liver and kidney cytoplasm where they form metallothioneins (the holo-protein forms) upon complexation with metal ions. Thi-onein synthesis is induced by the presence of metals, especially zinc, copper, mercury, and cadmium. 

The binding of transcription factors to nucleotide sequences, which facilitates gene transcription, can be influenced by chemicals. For example, cadmium binds to a metal-binding protein factor, MFF-1, in place of zinc and so induces metallothionein synthesis. This, as it happens is a detoxication, as metallothionein binds cadmium. 

The response of cells to stress (including reactive oxygen species and reactive metabolites) includes the upregulation of synthesis of stress proteins metallothioneins hsplOO, hsp 90, hsp70, hsp60, and hsp27. 

Elemental mercury is oxidized in vivo to inorganic mercury, a bio transformation that is probably catalyzed by catalase. It is selectively accumulated in the kidney and also by lysosomes. Inorganic mercury (Hg2+) will induce the synthesis of metallothionein. Mercury binds to cellular components such as enzymes in various organelles, especially to proteins containing sulfydryl groups. Thus, in the liver, cysteine and GSH will react with mercury to produce soluble products, which can be secreted into the bile or blood. 

We have seen (Section 56.1.13.2.2) that cadmium can induce the synthesis of a Cd-binding protein in fact, the administration of copper, zinc, cadmium or mercury to animals induces the synthesis of these proteins called metallothioneins, which play an important role in the metabolism of these elements. 

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. 

Foetal and neonatal livers contain exceptionally high levels of copper compared to the adult organ. Thus, the livers of new-born rats contain as much as 20 times the level of copper and zinc metallothionein as that found in 70-day-old rats.1150 Again, a metallothionein from foetal bovine liver contained eight copper and two zinc atoms per molecule of protein.1151 These proteins can only be isolated with difficulty under oxygen-free conditions. It appears then that large amounts of copper (and zinc) are stored in the liver bound to metallothionein, and are mobilized as required for enzyme synthesis after birth. 

Metallothionein Small molecular weight protein family, rich in cysteine, that binds strongly to divalent heavy metals. The synthesis is under the control of essential metals like zinc and copper. Other metals such as cadmium, mercury and silver can induce its concentration in cells. Volume 1(14). 

The second step in zinc absorption involves the intracellular interaction of zinc with various compounds which may enhance or impede absorptive processes. In 1969, Starcher noted that radioactive copper, given orally, associated with a low molecular weight protein (25). Subsequently, this mucosal protein was isolated and characterized by Richards and Cousins, who classified it as a metallothionein (26), and who further showed that it was induced in response to zinc administration (5). The appearance of this metallothionein, with properties similar to those described for both rat (27) and human (28) liver metallothionein, appears to be related to changes in both dietary zinc status and plasma zinc levels (5). The synthesis of mucosal metallothionein has been shown to be under transcriptional control (29,30). Menard al. reported that dietary zinc administration resulted in enhancement of metallothionein mRNA transcription and its subsequent translation, to yield nascent metallothionein polypeptides(31). The intestinal metallothionein appearance was correlated to both an increase in mucosal zinc content primarily associated with the protein and with a decrease in serum zinc levels. In addition. Smith e al., using the isolated, vascularly perfused intestinal system, reported an inverse relationship between the synthesis of metallothionein and zinc transfer to the portal system, confirming earlier studies (32). 

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