Metallothionein cadmium binding

The situation is different for other examples—for example, the peptide hormone glucagon and a small peptide, metallothionein, which binds seven cadmium or zinc atoms. Here large discrepancies were found between the structures determined by x-ray diffraction and NMR methods. The differences in the case of glucagon can be attributed to genuine conformational variability under different experimental conditions, whereas the disagreement in the metallothionein case was later shown to be due to an incorrectly determined x-ray structure. A re-examination of the x-ray data of metallothionein gave a structure very similar to that determined by NMR. 

Avdeef, A. Zelazowski, A. J. Garvey, J. S., Cadmium binding by biological ligands. 3. Five- and seven-cadmium binding in metallothionein A detailed thermodynamic study, Inorg. Chem. 24, 1928-1933 (1985). 

Metallothionein was first discovered in 1957 as a cadmium-binding cysteine-rich protein (481). Since then the metallothionein proteins (MTs) have become a superfamily characterized as low molecular weight (6-7 kDa) and cysteine rich (20 residues) polypeptides. Mammalian MTs can be divided into three subgroups, MT-I, MT-II, and MT-III (482, 483, 491). The biological functions of MTs include the sequestration and dispersal of metal ions, primarily in zinc and copper homeostasis, and regulation of the biosynthesis and activity of zinc metalloproteins. 

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. 

M. P. Waalkes, P. L. Goering, Metallothionein and other cadmium-binding proteins recent developments, Chem. Res. Toxicol., 3 (1990), 281-288. 

Metallothioneins (MTs) are a superfamily of low-molecular-weight (<7000-dalton) intracellular metal-binding proteins, which, in many species, play a critical role in (a) the detoxification of nonessential metals such as Cd2+ and Hg2+ and (b) the regulation of intracellular concentrations of essential metals such as Zn2+ and Cu+. In 1957, Kagi and Vallee first purified and characterized MT as a cadmium-binding protein in equine kidney. 

We have found that metallothionein, which selectively binds cadmium ion in vivo, binds gallium ion. The number of the gallium ion bound to one molecule of metallothionein, 26.6, was about twice as large as that of cadmium ion. The results of adsorption experiments to BSA, and the adsorption of various metal ions show that metallothionein selectively binds gallium ion. The specificity is very high because other metals which as similar ionic radius did not bound to the metallothinein as shown in Table 1. 

Squibb KS, Pritchard JB, Fowler BA. Cadmium metallothionein nephrotoxicity ultrastructural/biochemical alterations and intracellular cadmium-binding. J Pharmacol Exp Ther 1984 229 311-321. 

Nordberg GF, Jin T, Nordberg M. Subcellular targets of cadmium nephrotoxicity cadmium binding to renal membrane proteins in animals with or without protective metallothionein synthesis. Environ Elealth Perspect 1994 102 (suppi 3) 191-194. 

Cadmium is a classic cumulative poison that accumulates in the kidneys over a lifetime. It is transported in the blood by erythrocytes and by albumin, and it is stored mainly in the liver and kidneys as metallothionein (50-75% of the body burden). Cadmium binds to many proteins at the sulfate and carbonyl sites. The half-life of cadmium in these two organs may be as long as 30 years. The correlation between years of exposure and blood levels does not appear to be significant. Cadmium also accumulates in the bones and the placenta of pregnant women. 

Slice, L.W., Freedman, J.H. and Rubin, C. (1990) Purification, characterization, and cDNA cloning of a novel metallothionein-like, cadmium-binding protein from Caenorhabditis elegans. Journal of Biological Chemistry, 265, 256-263. 

Nordberg GF, Jin T, Nordberg M. Subcellular targets of cadmium nephrotoxicity cadmium binding to renal membrane proteins in animals with or without protective metallothionein synthesis. Environ Flealth Perspect 1994 102(suppl 3) 191-194. Fowler BA, Akkerman M. The role of Ca + + In cadmium-induced renal tubular cell Injury.. In Cadmium in the human environment toxicity and carcinogenicity. Nordberg G, Herber R, Alessio L (editors). International Agency for Research on Cancer (lARC) Scientific Publications vol 118, Lyon 1992 p. 271-277. 

Bernhard, W. R. Kagi, J. H. R. Purification and Characterization of Atypical Cadmium-Binding Polypeptides from ZeaMays. In Metallothionein II Kagi, J. H. R., Kojima, Y., Eds. Experientia Suppl. Birkhauser Verlag Basel, 1987 Vol. 52, pp 309-315. 

Digilio G, Bracco C, Vergani L et al (2009) The cadmium binding domains in the metallothionein isoform Cdy-MTIO from Mytilus galloprovincialis revealed by NMR spectroscopy. J Biol Inorg Chem 14 167-178... 

The over-refined food of highly industrialized countries seems to produce zinc deficiency in the elderly, characterized by loss of acuity in taste and slow healing of cuts and abrasions. The mammalian kidney has a protein, metallothionein, which binds excess of zinc, cadmium, or mercury (Rupp, Voelter and Weser, 1974). 

Aoki, Y., Kunimoto, M., Shibata, Y., and Suzuki, K. T. (1986) Detection of metallothionein on nitrocellulose membrane using Western blotting technique and its application to identification of cadmium-binding proteins. Anal. Biochem. 157, 117-122. 

The continuous synthesis of cadmium-binding metallothionein in the liver and kidneys will lead to cadmium being trapped there, and thus elimination is very slow. It has been estimated that less than 0.01% of the body burden is excreted daily, to a large extent via urine (Friberg et al., 1974), but also via bile and the gastrointestinal tract, saliva, skin, sweat, etc. (Molin and Wester, 1976 Elinder et al., 1978a, b Langmyhr et al., 1979). 

Riordan JR, Richards V (1980) Human fetal liver contains both copper-rich forms of metallothionein. J Biol Chem 255 5380-5383 Robbins AH, McRae DE, Williamson M, Collett SA, Xuong NH, Furey WF, Wang BC, Stout CD (1991) Refined crystal structure of Cd.Zn metallothionein at 2.0 A resolution. J Mol Biol 221 1269-1293 Rugstad HE, Norseth T (1975) Cadmium resistance and content of cadmium-binding protein in cultured human cells. Nature 257 136 Ryden L, Deutsch HF (1978) Preparation and properties of the major copperbinding component in human fetal liver. J Biol Chem 253 519-524 Sato M, Bremner I (1993) Oxygen free radicals and metallothionein. Free Radic Biol Med 14 325-337... 

Silar P, Butler G, Thiele DJ (1991) Heat shock transcription factor activates transcription of the yeast metallothionein gene. Mol Cell Biol 11 1232-1238 Squibb KS, Pritchard JB, Fowler BA (1984) Cadmium metallothionein nephropathy ultrastructural/biochemical alterations and intracellular cadmium binding. J Pharmacol Exp Ther 229 311-321... 

Van Eden W (1991) Heat-shock proteins as immunogenic bacterial antigens with the potential to induce and regulate autoimmune arthritis. Immunol Rev 121 5-28 Waalkes MP, Goering PL (1990) Metallothionein and other cadmium-binding proteins recent developments. Chem Res Toxicol 3 281-288 Waalkes MP, Ward JM (1989) Induction of hepatic metallothionein in male B6C3F1 mice exposed to hepatic tumor promoters effects of phenobarbital, acetaminophen, sodium barbital, and di(2-ethylhexyl) phthalate. Toxicol Appl Pharmacol 100 217-226... 

Mecfianisni of toxicologic damage. Cadmium induces the formation of metallothionein and binds to it in the tissues. The cadmium-metallothionein complex promotes renal accumulation. Metabolism releases free cadmium, which is nephrotoxic. 

After intravenous injection in experimental animals, cadmium in the blood is initially found mainly in the plasma, but later a shift takes place to r d blood cells, where the cadmium binds to proteins such as metallothionein and hemoglobin. Metallothionein is of great importance for the transport, excretion, and toxicity of cadmium. It was initially isolated firam equine r nal cortex and has a molecular weight of about 6000-7000. It can bind cadmium, zinc, and other metals owing to the presence of a large number of sulfhydryl gixrups and has been isolated from several tissues in man and animals. 

---