Copper thionein

Copper thionein Copper homeostasis Vertebrates Weser and Hartmann (1984)... 

Unlike the Cd, Zn-thioneins, the respective copper-thiolate proteins were much more susceptible to oxidation. The binding energy value of the S2p core electrons of yeast copper thionein lies at 162.0 eV (Fig. 5). Ageing of protein samples or the addition of substoichiometric concentrations of H2O2 give rise to the appearence to transient oxidation states including RSSR, RSO" and sulphonic acid. The copper thiolate... 

A reaction product of superoxide radicals is the reactive hydroxyl radical, which reacts with copper-thioneins as well [313]. However, the reaction of superoxide radicals with copper-thioneins can also create hydroxyl radicals it cannot be excluded that the oxidation of copper-thioneins by superoxide radicals or by other oxidants leads to the release of reactive Cu(II) ions [313]. These reactive Cu(II) ions could then, in an uncontrolled manner, convert more superoxide radicals to hydroxyl radicals, a process which possibly plays a role in inflammations. 

More copper is found in the brain and heart than in any other tissue except for liver, where it is stored as copper thionein and released as ceruloplasmin or in the form of a complex with serum albumin. The high metabolic rate of the heart and brain requires relatively large amounts of copper metalloenzymes including tyrosinase, cytochrome c oxidase, dopamine-/3-hydroxylase, pyridoxal-requiring monamine oxidases, and Cu-Zn superoxide dismutase. Copper deficiency, which can occur for reasons analogous to those discussed above for Fe and Zn, leads to brain disease in infants, anemia (since cytochrome oxidase is required for blood formation), and heart disease. Few details are known about the molecular basis for copper uptake from foods. 

As is also shown in Figure 6.1, an interleukin-1-mediated [29] acute-phase response to many diseases involves a release of copper-thioneine-stored copper from the liver as ceruloplasmin, copper amino-acid complexes, and a copper albumin complex to meet increased metabolic needs for copper, which exceed normal needs, and plasma copper concentrations increase 200-300% above normal, as illustrated in Figure 6.3. The appropriate increase coupled... 

Copper thioneins have two functions, namely, copper storage and detoxification. ... 

Bakka, A. and M. Webb. 1981. Metabolism of zinc and copper in the neonate changes in the concentrations and contents of thionein-bound Zn and Cu with age in the livers of the newborn of various mammalian species. Biochem. Pharmacol. 30 721-725. 

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 bound Zn and/or Cd ions to MT are readily released from the protein by acidification (pH 2) yielding the metal-free protein designated as thionein or apoMT. The release of tightly bound Cu from the MT structure requires more harsh conditions such as 0.5 M HCl or treatment with specific copper chelators. From H NMR and far-UV CD studies, apoMT was estimated to contain a predominantly disordered structure. From this protein form, a number of various metal derivatives have been prepared through the method of metal reconstitution (see Section 6.1). ... 

The mechanism of this eflFect is not known. Hill and Starcher (49) postulated that reduction of copper from its divalent (cupric) state to its monovalent (cuprous) state accounted for the impaired absorption of copper in the presence of ascorbic acid they produced the same effect with another reducing agent, dimercaptopropanol (BAL). This explanation has been accepted by others (56), although the oxidation state of copper for maximum intestinal absorption has not been established. An intramucosal competition of ascorbic acid for sulfhydryl sites on metallo-thioneins was demonstrated (57). If this ligand has any regulatory role in copper uptake, this alternative mechanism of ascorbic acid-copper interaction could explain the mechanism. Experimental confirmation of an ascorbic-acid-induced inhibition of copper absorption in the human intestine has not been presented. 

According to this model, all of the copper ions in Cu6-thionein are stably coordinated by four cysteine residues each. In Cu8-thioneins, an additional copper ion is added to each end of the Cu6-oligonuclear cluster. These two exposed positions are less stable, facilitating the extraction of the two copper ions. 

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. 

Hartmann HJ, Rupp H, Weser U (1979) Oxidation of copper and sulfur in Cu-thionein. In Metalloproteins, Weser U (ed), Georg Thieme, Stuttgart New York, p 207... 

Also shown in Figure 6.1, under homeostatic controlled conditions cop-per(I)-thioneine-stored copper is released from the liver in a circadian fashion... 

Mohan P, Failla M, Bremner I, Arthur-Smith A and Kerzner B (1995) Biliary copper excretion in the neonatal rat role of glutathione and metallo-thionein. Hepatology 21 1051-1057. 

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