F mercury toxicity 13 and bacterial r mercury is

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F. Mercury Toxicity 13 and Bacterial Resistance 14-17 Mercury is released into the environment as Hg(II) ions through weathering of its most common ore, HgS, red cinnabar. Organomercurials of general formula
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III. TOXIC EFFECT OF METALS 511 RHgX used in agriculture have also entered the environment as toxic waste. Both RHgX and HgX 2 compounds bind avidly to sulfhydryl groups in proteins, which can lead to neurological disease and kidney failure. Metallothionein is a favored protein target, which may help to limit mercury toxicity. A highly pub- licized case occurred in 1953 at Minimata, Japan, where 52 people died after eating mercury-contaminated fish and crustaceans near a factory waste outlet. The volatile, elemental form of mercury, Hg(O) , is reportedly nontoxic, but its conversion to alkylmercury compounds by anaerobic microorganisms utilizing a vitamin B-12 biosynthetic pathway constitutes a serious health hazard. Because of the high affinity of mercury for sulfur-donor ligands, mercury poisoning is treated by BAL; N-acetylpenicillamine has also been proposed. Recently, a very interesting natural detoxification system has been discovered in bacteria resistant to mercury; this system, when fully elucidated, might pro- vide important strategies for treating heavy-metal poisoning in humans. Presumably under environmental pressure, bacteria have developed mecha- nisms of resistance to HgX 2 and RHgX compounds in which mercury is recycled back to Hg(O). At least five gene products are involved in the bacterial mercury- resistance mechanism. MerT and MerP mediate the specific uptake of mercury compounds. MerB, organomercury lyase, and MerA, mercuric reductase, cata- lyze two of the reactions, given in Equations (9.1) and (9.2). Plasmids encoding the genes for these two proteins have been isolated. A typical arrangement of genes in the mer operon RHgX + H + + x- organomercury lyase ) HgX 2 + RH (9.1) mercuric Hg(SRh + NADPH + H + ~ Hg(O) + NADP + + 2RSH (9.2) region of these plasmids is shown in Figure 9.1. The most thoroughly studied gene product is MerR, a metalloregulatory protein that controls transcription of the mer genes. In the absence of Hg(II) the MerR protein binds to DNA as a repressor, preventing transcription of the merT, P, A, and B genes (Figure 9.1) and negatively autoregulating its own synthesis. When Hg(I1) is present, tran- scription of these genes is turned on. Interestingly, the MerR protein remains bound to the same site on DNA whether acting as an activator in the presence R A ~-~ B R, regulatory protein A, Hg(ll) - Hg(O) MerR reductase T, transport protein B, R-HgX - RH + Hg(lI) lyase P, periplasm- binding protein Figure 9.1 Arrangement of genes in mer operon of a gram negative bacterium (adapted from Figure 1, Reference 14).
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512 9 / METALS IN MEDICINE of Hg(II) or as a repressor in its absence. Random and site-specific mutagenesis studies implicate several cysteine residues in the carboxyl terminal region of the protein as candidates for the mercury-binding site.
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