The perceived importance of tellurium (Te) in biological systems has lagged behind selenium (Se), its lighter sister in the Group 16 chalcogens, because of tellurium's lower crustal abundance, lower oxyanion solubility and biospheric mobility and the fact that, unlike Se, Te has yet to be found to be an essential trace element. Te applications in electronics, optics, batteries and mining industries have expanded during the last few years, leading to an increase in environmental Te contamination, thus renewing biological interest in Te toxicity. This chalcogen is rarely found in the nontoxic, elemental state (Te(0)), but its soluble oxyanions, tellurite (TeO(3)(2-)) and tellurate (TeO(4)(2-)), are toxic for most forms of life even at very low concentrations. Although a number of Te resistance determinants (Tel) have been identified in plasmids or in the bacterial chromosome of different species of bacteria, the genetic and/or biochemical basis underlying bacterial TeO(3)(2-) toxicity is still poorly understood. This review traces the history of Te in its biological interactions, its enigmatic toxicity, importance in cellular oxidative stress, and interaction in cysteine metabolism.

Biochemical, genetic, enzymatic and molecular approaches were used to demonstrate, for the first time, that tellurite (TeO3 2−) toxicity in E. coli involves superoxide formation. This radical is derived, at least in part, from enzymatic TeO3 2− reduction. This conclusion is supported by the following observations made in K2TeO3-treated E. coli BW25113: i) induction of the ibpA gene encoding for the small heat shock protein IbpA, which has been associated with resistance to superoxide, ii) increase of cytoplasmic reactive oxygen species (ROS) as determined with ROS-specific probe 2′7′-dichlorodihydrofluorescein diacetate (H2DCFDA), iii) increase of carbonyl content in cellular proteins, iv) increase in the generation of thiobarbituric acid-reactive substances (TBARs), v) inactivation of oxidative stress-sensitive [Fe-S] enzymes such as aconitase, vi) increase of superoxide dismutase (SOD) activity, vii) increase of sodA, sodB and soxS mRNA transcription, and viii) generation of superoxide radical during in vitro enzymatic reduction of potassium tellurite.

Reactive oxygen species damage intracellular targets and are implicated in cancer, genetic disease, mutagenesis, and aging. Catalases are among the key enzymatic defenses against one of the most physiologically abundant reactive oxygen species, hydrogen peroxide. The well-studied, heme-dependent catalases accelerate the rate of the dismutation of peroxide to molecular oxygen and water with near kinetic perfection. Many catalases also bind the cofactors NADPH and NADH tenaciously, but, surprisingly, NAD(P)H is not required for their dismutase activity. Although NAD(P)H protects bovine catalase against oxidative damage by its peroxide substrate, the catalytic role of the nicotinamide cofactor in the function of this enzyme has remained a biochemical mystery to date. Anions formed by heavy metal oxides are among the most highly reactive, natural oxidizing agents. Here, we show that a natural isolate of Staphylococcus epidermidis resistant to tellurite detoxifies this anion thanks to a novel activity of its catalase, and that a subset of both bacterial and mammalian catalases carry out the NAD(P)H-dependent reduction of soluble tellurite ion (TeO3 2−) to the less toxic, insoluble metal, tellurium (Te°), in vitro. An Escherichia coli mutant defective in the KatG catalase/peroxidase is sensitive to tellurite, and expression of the S. epidermidis catalase gene in a heterologous E. coli host confers increased resistance to tellurite as well as to hydrogen peroxide in vivo, arguing that S. epidermidis catalase provides a physiological line of defense against both of these strong oxidizing agents. Kinetic studies reveal that bovine catalase reduces tellurite with a low Michaelis-Menten constant, a result suggesting that tellurite is among the natural substrates of this enzyme. The reduction of tellurite by bovine catalase occurs at the expense of producing the highly reactive superoxide radical.

Many eubacteria are resistant to the toxic oxidizing agent potassium tellurite, and tellurite resistance involves diverse biochemical mechanisms. Expression of the iscS gene from Geobacillus stearothermophilus V, which is naturally resistant to tellurite, confers tellurite resistance in Escherichia coli K-12, which is naturally sensitive to tellurite. The G. stearothermophilus iscS gene encodes a cysteine desulfurase. A site-directed mutation in iscS that prevents binding of its pyridoxal phosphate cofactor abolishes both enzyme activity and its ability to confer tellurite resistance in E. coli. Expression of the G. stearothermophilus iscS gene confers tellurite resistance in tellurite-hypersensitive E. coli iscS and sodA sodB mutants (deficient in superoxide dismutase) and complements the auxotrophic requirement of an E. coli iscS mutant for thiamine but not for nicotinic acid. These and other results support the hypothesis that the reduction of tellurite generates superoxide anions and that the primary targets of superoxide damage in E. coli are enzymes with iron-sulfur clusters.The cytoplasm is a reducing environment, and many oxidizing agents can cause cellular damage by covalently modifying intracellular targets. Among these, the tellurite oxyanion (TeO 3 2Ϫ ) is toxic to most microbes. Tellurite can cross the gram-negative membrane using systems involved in phosphate uptake (28) and is a substrate for nitrate reductase, which can reduce the anion to tellurium, which is insoluble and nontoxic (3).To understand the basis of tellurite toxicity at the molecular level, we are exploring the mechanisms by which microbes are resistant to this anion. Several bacteria are naturally resistant to potassium tellurite, and both the genetic and biochemical bases of this resistance appear to be diverse. Tellurite resistance determinants are found both in bacterial chromosomes and in plasmids (22,27).The gram-positive bacterium Geobacillus stearothermophilus V, formerly Bacillus stearothermophilus V (16), is naturally resistant to high levels of tellurite (30, 31). Our work has focused on the identification and characterization of G. stearothermophilus genes that confer tellurite resistance when expressed in Escherichia coli. We have constructed gene libraries from G. stearothermophilus in high-copy-number plasmids, transformed sensitive E. coli hosts with these libraries, and selected for tellurite-resistant clones. Using this strategy, Vásquez et al. have found that the cysK gene of G. stearothermophilus confers a tellurite resistance phenotype in E. coli (30,31). CysK catalyzes the synthesis of cysteine from O-acetyl serine and sulfide as substrates, the terminal, rate-limiting step in cysteine biosynthesis. The cysK genes from other microorganisms have also been shown to confer tellurite resistance in E. coli (1,17).In this paper, we show that the expression of G. stearothermophilus cysteine desulfurase (IscS), a second enzyme involved in cysteine metabolism, also confers tellurite resistance in E. coli. Cysteine desul...

Tellurite exerts a deleterious effect on a number of small molecules containing sulfur moieties that have a recognized role in cellular oxidative stress. Because cysteine is involved in the biosynthesis of glutathione and other sulfur-containing compounds, we investigated the expression of Geobacillus stearothermophilus V cysteinerelated genes cobA, cysK, and iscS and Escherichia coli cysteine regulon genes under conditions that included the addition of K 2 TeO 3 to the culture medium. Results showed that cell tolerance to tellurite correlates with the expression level of the cysteine metabolic genes and that these genes are up-regulated when tellurite is present in the growth medium.Sulfur is an essential element that is required for the biosynthesis of proteins, enzyme cofactors, and other important biomolecules. In bacteria, this element can be assimilated into sulfur-containing amino acids through enzymatic fixation from inorganic sources, such as sulfate and/or thiosulfate (15, 38). Although tellurium shares several chemical properties with sulfur, no biological function for Te is known to date. Conversely, some tellurium compounds, like the oxyanion tellurite (TeO 3 2Ϫ ), are extremely toxic for most forms of life, especially microorganisms (34).It has been proposed that K 2 TeO 3 toxicity could be due to the oxidation of cellular thiols such as glutathione (37) or the generation of superoxide radical during tellurite reduction, which would cause a redox imbalance resulting in intracellular oxidative stress (5,23,26,33,34,36).Maintenance of cell redox balance is one of the most important processes involving molecules synthesized from reduced sulfur taken from the environment. Glutathione (GSH) is one of the major nonprotein thiols in living organisms, including humans, yeast, and bacteria (6, 10). GSH has been involved in resistance to osmotic and oxidative stress as well as in Escherichia coli resistance to the toxic effects of electrophiles like methylglyoxal (6,11,31). A protective effect of GSH against oxidative stress has also been described for Lactococcus lactis and Rhodobacter capsulatus (17,18).Three genes involved in tellurite resistance have been described previously for the thermotolerant gram-positive rod Geobacillus stearothermophilus V (27, 33, 41). The genes that are involved in the metabolism of cysteine are cysK, iscS, and cobA, and they encode a cysteine synthase (CysK), a cysteine desulfurase (IscS), and a uroporphyrinogen-III C-methyltransferase (SUMT), respectively. CysK catalyzes the last step of inorganic sulfur fixation into L-cysteine, while SUMT is involved in the biosynthesis of siroheme, an essential sulfite reductase cofactor that participates in the inorganic assimilation of sulfur (15). We recently demonstrated that cobA and ubiE genes from G. stearothermophilus V confer increased tolerance to oxyanions of selenium and tellurium when expressed in E. coli (1, 32). Finally, IscS, which yields sulfur and L-alanine from L-cysteine, has been shown to be involved, along with IscA ...