Binding metallothioneins

There is concern over the toxicity of a nnmber of metals and metalloids, and their oxyanions. As for antibiotics, the genes for resistance are often plasmid-bome. There are several mechanisms that may operate—redaction, methylation, efflnx, and the synthesis of metal-binding metallothioneins. The following text illustrates aspects of these mechanisms. 

The detection of metal-binding proteins, especially of Cd- and Hg-binding metallothioneins or of the merR protein, induced numerous studies of model compounds of Cd and Hg with more or less simple sulfur- and selenium-containing ligands. 

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). 

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. 

Cadmium, 5, 925-1022 acute poisoning, 5,1000 binding to metallothioneins, 6, 673 chronic poisoning, 5, 1000 gravimetry, 1,532 masking, 1,538 metallothioneins, 5,1021 poisoning... 

Metallothioneins are a group of small proteins (about 6.5 kDa), found in the cytosol of cells, particularly of liver, kidney, and intestine. They have a high content of cysteine and can bind copper, zinc, cadmium, and mercury. The SH groups of cysteine are involved in binding the metals. Acute intake (eg, by injection) of copper and of certain other metals increases the amount (induction) of these proteins in tissues, as does administration of certain hormones or cytokines. These proteins may function to store the above metals in a nontoxic form and are involved in their overall metaboHsm in the body. Sequestration of copper also diminishes the amount of this metal available to generate free radicals. 

Metallothioneins (MTs) are small proteins with an especial affinity for the binding of various heavy metals active in a wide range of reactions [95-97]. Besides their role in... 

Otvos, J.D., Petering, D.H. and Shaw, C.F. Ill (1989) Structure - Reachvity Relationships of Metallothionein, a Unique Metal-Binding Protein. Comments on Inorganic Chemistry, 9,1-35. 

Teigen SW, Andersen RA, Daae HL, Skaare JU. 1999. Heavy metal content in liver and kidneys of grey seals Halichoerus grypus) in various life stages correlated with metallothionein levels some metal-binding characteristics of this protein. Environ Toxicol Chem 18 2364-2369. 

Metallothioneins are a group of non-enzymatic, low-molecular mass (6-7 kDa) metal-binding proteins. They play an important role in the detoxification of a number (Zn, Cu, Cd, and Hg) of trace metals (Chassaigne and Lobinski 1998). 

Mammalian metallothioneins typically bind seven metal ions in cluster structures, with bridging sulfur groups, as seen in the x-ray structure of the Cd5Zn2MT complex (86). It is therefore difficult to develop a simple formation-constant description for the binding of metal ions to MT (87), considering that protonation-deprotonation equilibria of the free protein itself should also be taken into account. However, the usefulness of Table VIII as a guide to the affinity of metal ions for mercapto donor ligands is seen in that the ability of metal ions to... 

Metabolism. As noted in Section 3.4.3, the metabolism of americium consists of binding interactions with proteins and probably complex formation with various inorganic anions such as carbonate and phosphate, and carboxylic acids such as citrate and lactate (Durbin 1973 Taylor 1973 Webb et al. 1998). Experiments have not been conducted to determine whether americium binds to metallothionein, but such binding is not likely. 

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). 

It is now established that cadmium, besides zinc, is accumulated in some native cysteine-rich proteins (e.g., metallothioneins) and the binding mode and sites in the protein are studied and largely understood.57 Also, the detection and study of native Cd-enzymes and Cd-substituted Zn-enzymes is just beginning at the time of writing (for a short survey see ref. 58). 

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). 

Chan, J. Huang, Z. Merrifield, M. E. Salgado, M. T. Stillman, M. J. Studies of metal binding reactions in metallothioneins by spectroscopic, molecular biology, and molecular modeling techniques. Coord. Chem. Rev. 2002,... 

Metallothioneins (MT) are unique 7-kDa proteins containing 20 cysteine molecules bounded to seven zinc atoms, which form two clusters with bridging or terminal cysteine thiolates. A main function of MT is to serve as a source for the distribution of zinc in cells, and this function is connected with the MT redox activity, which is responsible for the regulation of binding and release of zinc. It has been shown that the release of zinc is stimulated by MT oxidation in the reaction with glutathione disulfide or other biological disulfides [334]. MT redox properties led to a suggestion that MT may possesses antioxidant activity. The mechanism of MT antioxidant activity is of a special interest in connection with the possible antioxidant effects of zinc. (Zinc can be substituted in MT by some other metals such as copper or cadmium, but Ca MT and Cu MT exhibit manly prooxidant activity.)... 

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