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The structure of metallothionein, its two domains, and binding sites. Cysteine residues with-SH groups are marked in yellow; contribution of these groups in metal binding is evident (A). The biologically important isoforms of metallothionein gene in human (B).
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Zinc as an essential element plays the crucial role in many physiological, but also pathological processes - zinc controls cell proliferation, differentiation, and viability including the apoptosis. These facts are especially based on the structural role of zinc ions in many proteins including the transcription factors. Due to the role of zinc in m...
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Context 1
... crucial role in the zinc homeostasis play major zinc binding proteins metallothioneins (44), which participate in the regulation of free zinc ions and their nuclear translocation during the cell cycle and processes of cell differentiation ( Figure 1A) (1). Metallothioneins (MTs) belong to the group of the ubiquitous intracellular low-molecular proteins of molecular weight between 6 and 10 kDa. ...
Context 2
... were discovered as the cadmium-binding protein isolated from the horse kidneys. The human MT gene family consists of 18 isoforms, containing pseudogenes as well as the genes encoding the functional proteins ( Figure 1B). MTs have high affinity to the divalent ions, such as the toxicologically important cadmium and mercury, but also to the essential copper and zinc ions. ...
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Citations
... In contrast, MT-3 and MT-4 are non-inducible proteins, with their expression primarily confined to the central nervous system (CNS) and certain squamous epithelia, respectively. MT-1 through MT-3 have been reported to be secreted, suggesting that they may play different biological roles in the intracellular and extracellular space [28]. In the postgenomic era, it is becoming increasingly clear that MTs fulfil multiple functions, including the involvement in zinc and copper homeostasis, protection against heavy metal toxicity. ...
Prion and other amyloid-forming diseases represent a group of neurodegenerative disorders that affect both animals and humans. The role of metal ions, especially copper and zinc is studied intensively in connection with these diseases. Their involvement in protein misfolding and aggregation and their role in creation of reactive oxygen species have been shown. Recent data also show that metal ions not only bind the proteins with high affinity, but also modify their biochemical properties, making them important players in prion-related diseases. In particular, the level of zinc ions is tightly regulated by several mechanisms, including transporter proteins and the low molecular mass thiol-rich metallothioneins. From four metallothionein isoforms, metallothionein-3, a unique brain-specific metalloprotein, plays a crucial role only in this regulation. This review critically evaluates the involvement of metallothioneins in prion- and amyloid-related diseases in connection with the relationship between metallothionein isoforms and metal ion regulation of their homeostasis.
... 125 They are principally localized intracellularly, usually attached to Golgi membranes, but recently MTs have been found extracellularly, and under certain conditions they translocate to the nucleus. 126 MT transcription is regulated by zinc, but the protein can bind both essential (e.g. zinc and copper) and non-essential metals through the thiol groups. ...
A general principle in all cells in the body is that an essential metal – here copper – is taken up at the plasma membrane, directed through cellular compartments for use in specific enzymes and pathways, stored in specific scavenging molecules if in surplus, and finally expelled from the cells. Here we attempt to provide a critical view on key concepts involved in copper transfer across membranes and through compartments in the human body. The focus of this review is on the influence of bioinorganic and thermodynamic rules on the flow in cellular copper networks. Transition of copper from one oxidation state to another will often lead to errant electrons that are highly reactive and prone to form radicals and reactive oxygen or nitrogen species (ROS and RNS). Strict control of potentially toxic oxidative species is an important part of understanding the edge of human copper metabolism. The present review critically covers translocation across simple and complex membranes as well as extracellular and intracellular copper routing. We discuss in depth four tissues with polarized cell barriers – the gut, liver, kidneys, and brain – to illustrate the similarities and differences in transcellular transfer. Copper chaperoning, buffering and binding dynamics to guide the metal to different sites are also covered, while individual molecular interaction kinetics are not detailed. Sorting and targeting mechanisms and principles crucial for correct localisation will also be touched upon.
... Nevertheless, during this process, cysteine is oxidized to cystine, with subsequent release of the metal ions which were previously bound to cysteine. Metallothioneins control zinc ion signaling and are involved in the regulation of the tumor suppressor protein p53: co-expression of metallothioneins and p53 and their complex formation in tumor cells, may be involved in regulation of apoptosis in breast cancer epithelial cells [154,155]. ...
This Review Article is focused on the action of the reactive oxygenated species in inducing oxidative injury of the lipid membrane components, as well as on the ability of antioxidants (of different structures and sources, and following different mechanisms of action) in fighting against oxidative stress. Oxidative stress is defined as an excessive production of reactive oxygenated species that cannot be counteracted by the action of antioxidants, but also as a perturbation of cell redox balance. Reactive oxygenated/nitrogenated species are represented by superoxide anion radical, hydroxyl, alkoxyl and lipid peroxyl radicals, nitric oxide and peroxynitrite. Oxidative stress determines structure modifications and function modulation in nucleic acids, lipids and proteins. Oxidative degradation of lipids yields malondialdehyde and 4-hydroxynonenal, but also isoprostanes, from unsaturated fatty acids. Protein damage may occur with thiol oxidation, carbonylation, side-chain oxidation, fragmentation, unfolding and misfolding, resulting activity loss. 8-hydroxydeoxyguanosine is an index of DNA damage. The involvement of the reactive oxygenated/nitrogenated species in disease occurrence is described. The unbalance between the oxidant species and the antioxidant defense system may trigger specific factors responsible for oxidative damage in the cell: over-expression of oncogene genes, generation of mutagen compounds, promotion of atherogenic activity, senile plaque occurrence or inflammation. This leads to cancer, neurodegeneration, cardiovascular diseases, diabetes, kidney diseases. The concept of antioxidant is defined, along with a discussion of the existent classification criteria: enzymatic and non-enzymatic, preventative or repair-systems, endogenous and exogenous, primary and secondary, hydrosoluble and liposoluble, natural or synthetic. Primary antioxidants are mainly chain breakers, able to scavenge radical species by hydrogen donation. Secondary antioxidants are singlet oxygen quenchers, peroxide decomposers, metal chelators, oxidative enzyme inhibitors or UV radiation absorbers. The specific mechanism of action of the most important representatives of each antioxidant class (endogenous and exogenous) in preventing or inhibiting particular factors leading to oxidative injury in the cell, is then reviewed. Mutual influences, including synergistic effects are presented and discussed. Prooxidative influences likely to occur, as for instance in the presence of transition metal ions, are also reminded.
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... Metallothionein is involved in many cellular functions, particularly in the transport, storage and detoxification of metals, metabolism of essential metals and uptake of the free radicals (Babula et al., 2010;Krizkova et al., 2012;Ryvolova et al., 2012;Pekarik et al., 2013). Formation of metallothionein-metal complexes protects the organism mainly against acute toxic effects of metals (Waalkes et al., 1984). ...
In this study, we focused on the effect of heavy metal ions in resistant strains of gram-positive bacteria Staphylococcus aureus using biochemical methods and mass spectrometry. Five nitrate solutions of heavy metals (Ag+, Cu2+, Cd2+, Zn2+ and Pb2+) were used to create S. aureus resistant strains. Biochemical changes of resistant strains in comparison with the non-resistant control strain of S. aureus were observed by microbiological (measuring - growth curves and inhibition zones) and spectrophotometric methods (antioxidant activity and alaninaminotransferase, aspartateaminotransferase, alkaline phosphatase, γ-glutamyltransferase activities). Mass spectrometry was employed for the qualitative analysis of the samples (changes in S. aureus protein composition) and for the identification of the strains database MALDI Biotyper was employed. Alterations, in terms of biochemical properties and protein composition, were observed in resistant strains compared to non-resistant control strain. Our results describe the possible option for the analysis of S. aureus resistant strains and may thus serve as a support for monitoring of changes in genetic information caused by the forming of resistance to heavy metals.
... These spots are probably zincosomes, compartments of endoplasmic reticulum origin. 16 2.3.2 Determination of free thiols. ...
Zinc(II) ions are important components of many proteins and are involved in numerous cellular processes such as apoptosis or drug resistance. Prostate cancer has a unique relationship with zinc(II) ions. However, the relationship was examined only in short-term zinc(II) treatments. Therefore, the aim of this study was to create zinc-resistant prostatic cell lines at various stages of the disease (22Rv1 and PC-3) and a normal prostate epithelium (PNT1A) using a long-term zinc exposure. Consequently, the expression profile was analyzed of the following genes: BAX, Bcl-2, Beclin-1, CFLAR, HIF1[small alpha], KRAS, mTOR, MT1A, MT2A, NF-[small kappa]B1, p53, survivin, ZIP1, ZnT-1. The resistance was verified using the MTT test; on average a 1.35-fold lower zinc (II) toxicity (higher IC50) was determined in zinc(II)-resistant cells. The associated resistance to cisplatin was also determined; IC50 for cisplatin was 1.52-fold higher. With regard to the gene expression profiles, our results indicate that differe
... MT is an intracellular protein rich for cysteine residua Krizkova et al., 2009;Adam et al., 2010a;Babula et al., 2010Babula et al., , 2012Ryvolova et al., 2011). It is both antioxidant being able to undergo to oxidized form and a chelator of heavy metals (Masarik et al., 2011Sochor et al., 2012a). ...
Taurine (2-aminoethanesulfonic acid) is an organic acid widely distributed in animal tissues. It is involved in many physiological processes. Thus, it is widely discussed especially due to its antioxidant properties. In this study, we focused on the effect of taurine supplementation on the concentration of antioxidants in blood plasma and erythrocytes of Wistar rats. Taurine was applied in feed mixture in the dosage of 0, 1, 250, 500, 750, 1000, 1500, 2000, 2500, 3000, 3500 and 4000 mg/kg. We monitored both enzymatic and non-enzymatic antioxidants – glutathione peroxidase, glutathione reductase, and superoxide dismutase and reduced/oxidized glutathione and metallothionein. Using three different methods 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), Ferric Reducing Antioxidant Power (FRAP) and free radicals, we determined antioxidant capacity. In addition, we monitored levels of uric acid and glucose. Our results revealed significant changes in both enzymatic and non-enzymatic parameters with the increasing taurine supplementation.
... This is similar to experiments where possible interactions of intercalating agents, such as ethidium bromide with DNA, are monitored with fluorescent intensity. Our study shows that zinc(II) ions may interact directly with DNA (binding to DNA), or may regulate gene expression, which is consistent with previously published data [54] . Stabilizing the interactions between MTF-I and MT promoter in response to metals may involve the recruitment of chromatin remodeling factors as well as increased affinity and specificity of DNA binding in response to zinc occupancy and/or post-translational modifications [20]. ...
... In mammals, these proteins may serve as a reservoir of metals (mainly zinc and copper) for the synthesis of apoenzymes and zinc-finger transcription regulators. Moreover, new roles of these proteins have been discovered including those needed in the carcinogenic process [5][6][7][8][9][10]. Isolation, separation, detection, and/or quantification of MT are not easy tasks for modern bioanalytical chemistry. ...
Prostate cancer with altered zinc(II) cell metabolism is the second most frequently diagnosed cancer in developed countries. The alterations of zinc(II) metabolism can influence metabolism of other metal ions and can also be associated with the expression and translation of metal-binding proteins including metallothioneins. The aim of this article was to optimize immunoseparation protocol based on paramagnetic beads conjugated with protein G for the isolation of metallothionein. Isolated metallothionein was determined by differential pulse voltammetry Brdicka reaction and SDS-PAGE. Optimal conditions: antigen-binding time - 60 min, temperature - 70°C, and buffer composition and pH - acetate buffer, pH 4.3, were determined. Under the optimized conditions, lysates from 22Rv1 prostate cancer cells treated with various concentrations of cadmium(II) and copper(II) ions were analyzed. We observed strong correlation in all experimental groups and all lysate types (r>0.83 at p<0.041) between metallothionein concentration related to viability and concentration of copper(II) ions and cadmium(II) ions in medium. Moreover, the results were compared with standard sample preparation as heat treatment and SDS-PAGE analysis.
... Z tohoto dÛvodu je hladina metalothioneinu v cytoplasmû bunûk niωí. Vzhledem k jeho vztahu k zineãnat˘m iontÛm, jejichÏ metabolismus je u karcinomu prostaty patologick˘, je moÏné oãekávat, Ïe se metalothionein mÛÏe podílet na patogenezi onemocnûní (7,19). ...
Current methods for diagnosis of prostate carcinoma do not enable us to distinguish aggressive tumours (significant tumours) from clinically latent tumours (non-significant tumours). This study aims to determine levels of potential clinically important tumour markers such as ◆ alpha-methyl CoA-racemase (AMACR), ◆ caveolin-1, ◆ metallothionein (MT), ◆ p53, ◆ NF-κB, ◆ c-FOS, ◆ c-JUN, ◆ Ki-67, ◆ prostate-specific antigen (PSA), ZIP1 and ZnT-1 in prostatic tissue represented by 22Rv1 (tumour) and PNT1A (healthy) cell lines and in blood serum of patients with histologically evaluated adenocarcinoma (82 tumour patients and 51 healthy volunteers). Based on mRNA expression, it was found that Cav-1, NF-κB, c-FOS and c-JUN were down-regulated and MT, AMACR, PSA, Ki-67, MMP-9 and zinc transporters ZIP1 and ZnT-1 were up-regulated. In serum, the level of MT was significantly enhanced above 1 μM. Caveolin-1 levels were significantly increased in high-grade tumours, which points to the possibility of using this protein as a marker for the aggressive form of prostate carcinoma.
Zinc is an essential trace element next to iron in the human system. Its central role in the synthesis, storage, and functional aspects of insulin is well established. Ever since the insulin-mimetic activity of zinc was recognized, several zinc complexes have been synthesized and studied for their antidiabetic and other pharmacological properties. However, its clinical application is narrow due to poor absorption, toxicity associated with prolonged use. Hence, endeavors are being made for the advancement of zinc complexes with various organic ligands of known therapeutic values to avert the toxicity of zinc. Avicularin, a bioactive flavonol originally isolated from the leaves of Polygonum aviculare Linn., is a quercetin derivative in which the α-L-arabinofuranosyl residue is linked at position 3 of quercetin via a glycosidic linkage. It is non-toxic and reported to possess a wide range of pharmacological properties. Though Avicularin is a glycoside of quercetin, it is hydrophilic while quercetin is lipophilic and hence they may differ in absorption rate. In view of the beneficial and pharmacological properties bestowed with Avicularin, recently we have reported the synthesis, spectral characterization and evaluation of antidiabetic properties of a new Zn-Avicularin complex in HFD fed low dose STZ induced experimental type 2 diabetes in rats. In the present study, an attempt has been made to evaluate the antioxidant properties of the Zn-Avicularin complex by analyzing the levels of oxidative stress markers such as lipid peroxides, hydroperoxides and protein carbonyls in the plasma, pancreas, hepatic and renal tissues. The status of enzymatic antioxidants such as SOD, catalase, Glutathione peroxidase as well as non-enzymatic antioxidants such as vitamin C, vitamin E and ceruloplasmin were assayed. Oral administration of the Zn-Avicularin complex at a concentration of 5mg/kg b.w/rat/day for 30 days significantly ameliorates the hyperglycemia-induced oxidative stress in the diabetic groups of rats and the efficacy was comparable with metformin.
