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All organisms require trace amounts of metal ions, such as copper, iron, and zinc, since they form an essential component of a number of enzymes. In the past few years many metal-responsive transcriptional regulators have been identified in both prokaryotes and eukaryotes, which can be grouped in distinct families, based on their evolutionary and structural relationships. By regulating systems involved in metal uptake as well as metal efflux and sequestering, these transcription factors help to maintain a delicate balance between necessity and toxicity. Despite the structural similarities within the transcription factor families, individual members can have an affinity for different, and sometimes multiple, metal substrates. The recent availability of crystal structures for key members has led to a detailed understanding of the origins of metal specificity and the mechanisms of transcriptional activation for most of these transcription factor families.

Toxic metals are an integral part of our environment and all organisms possess systems to evade toxicity and acquire tolerance. Studies in yeast have revealed a number of important tolerance systems encompassing metal uptake and export pathways, metal binding and sequestration systems as well as the regulatory mechanisms that the cell utilizes to control these systems. The study of the physiological, molecular, and genetic details of the function of these systems has significantly contributed to our understanding of toxic metal tolerance acquisition. This review will focus on tolerance mechanisms to toxic metals including cadmium, arsenic, antimony, mercury, and selenium in the model eukaryote Saccharomyces cerevisiae (bakers’ yeast) and other fungi.

Nonessential metals are opportunistic. They compete with essential metals for binding to various cofactors, receptors, transcription factors, transporters, and other metalloproteins, and in doing so they gain access to various cellular and subcellular compartments, and interfere in the functions of the essential metals. Because of their high chemical reactivities, nonessential metals also interact nonspecifically with a multitude of other cellular ligands, and interfere with many other cellular processes. In general, nonessential metals cross biological membranes by three mechanisms. First, as indicated above, they often compete with endogenous metals for transport on the various metal ion transporters, pumps, and channels. Alternatively, they may form complexes that are then substrates for other ion and organic solute transporters and pumps. A third general mode of transport involves both signal-induced (e.g. receptor-mediated) and constitutive endocytosis of metals ions and metal complexes. In contrast with these mediated transport pathways, simple diffusion appears to play only a minor role in metal transport. Collectively, these permeation pathways allow toxic metals to reach diverse cellular and subcellular targets, but can also be exploited in the design of therapeutic strategies aimed at accelerating the removal of these toxic elements from the body.

This chapter reviews basic concepts in metal biology and suggests a vision for the future of metals in medicine. Important developments in the field include the discovery of metallochaperones that prevent free metals from reeking havoc inside of cells. These intracellular metal ion carriers may work in conjunction with scaffold proteins or may deliver their cargo directly to metalloenzymes or metal transport proteins. Another area reviewed is the mechanism of metalloid uptake and detoxification. This leads into the future of metals in medicine, using examples from past and recent history.