![]() ![]() 4 Human zinc deficiency causes a myriad of symptoms, including diarrhea, alopecia, immune system impairment, chronic inflammation, compromised physical growth and development, neurological deficits and impaired reproductive development. ![]() 2, 3 Zinc deficiency is a global public health problem, leaving ~2 billion people at risk for deficiency of this trace metal. The essentiality of zinc as a trace nutrient was first discovered in the fungus Aspergillus niger in 1869, but it was nearly a century later that zinc was found to be an essential micronutrient for humans. 1 Thus, the chemical properties of zinc are ideal for its many biological roles. 1 Zinc shows flexible and dynamic coordination geometry with nitrogen, oxygen and sulfur ligands present in histidine, glutamate, aspartate and cysteine residues in proteins. Zinc is maintained in the Zn 2+ state under all biologically relevant redox potentials and pH conditions. Within a cell, zinc is redox-inert and has a valence state of +2. Zinc is the second most abundant transition metal in the human body. As zinc is emerging as an important signaling molecule in the development and progression of cancer, the ZnT and ZIP transporters that regulate cellular zinc homeostasis are promising candidates for targeted cancer therapy. Here we review recent progress toward understanding the structural basis for zinc transport by ZnT and ZIP family proteins, as well as highlight the roles of zinc as a signaling molecule in physiological conditions and in various cancers. Zinc dyshomeostasis has been implicated in the progression of cancer. Consequently, changes in zinc transporter localization and function resulting in zinc dyshomeostasis have pathophysiological effects. Fluctuations in intracellular zinc levels mediated by these transporter families affect signaling pathways involved in normal cell development, growth, differentiation and death. ![]() Cellular zinc homeostasis involves the opposing action of two families of metal transporters: the ZnT (SLC30) family that functions to reduce cytoplasmic zinc concentrations and the ZIP (SLC39) family that functions to increase cytoplasmic zinc concentrations. Zinc is an essential micronutrient that plays a role in the structural or enzymatic functions of many cellular proteins. Hence, these proteins represent important therapeutic targets for drug discovery. Not only dysregulation or dysfunction of P-type ATPases, but also mutations in their genes are often associated with human diseases. The members of the P-type ATPases share a general characteristic architecture and working mechanism but, at the same time, are unique proteins through their specificity to the substrate, mode of regulation, subcellular localization and tissue distribution. Therefore, they allow interaction between the extracellular and intracellular environment and serve as critical mediators of physiological activities of cells and organelles. They play a key role in a broad range of cellular functions such as generating vitally important ion gradients, uptake or extrusion of heavy metals or polyamines, controlling lipid asymmetry and vesicle formation in membranes. P-type ATPases operate as molecular pumps in cells and transport various substrates across biological membranes using ATP as the energy source. ![]()
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