Zinc homeostasis

It has been demonstrated that extremely tight control is exhibited over the intracellular zinc concentrations by the metalloregulatory proteins controlling zinc homeostasis. It had previously been thought that intracellular zinc was available in a pool of free zinc ions in the micro- to pico-molar concentration. An important study shows that these concentrations of free zinc are inconsistent with the concentrations required to trigger zinc uptake.974... 

In mammals, as in yeast, several different metallothionein isoforms are known, each with a particular tissue distribution (Vasak and Hasler, 2000). Their synthesis is regulated at the level of transcription not only by copper (as well as the other divalent metal ions cadmium, mercury and zinc) but also by hormones, notably steroid hormones, that affect cellular differentiation. Intracellular copper accumulates in metallothionein in copper overload diseases, such as Wilson s disease, forming two distinct molecular forms one with 12 Cu(I) equivalents bound, in which all 20 thiolate ligands of the protein participate in metal binding the other with eight Cu(I)/ metallothionein a molecules, with between 12-14 cysteines involved in Cu(I) coordination (Pountney et ah, 1994). Although the role of specific metallothionein isoforms in zinc homeostasis and apoptosis is established, its primary function in copper metabolism remains enigmatic (Vasak and Hasler, 2000). 

In a normal human adult, about 2 g of zinc is filtered by the kidneys daily and about 0.3 to 0.6 mg is actually excreted each day (Goyer 1986). Zinc homeostasis in rats, unlike most mammals, is maintained by zinc secretion from the intestines rather than by regulation of zinc absorption (Elinder 1986). Initial uptake of zinc from the rat gastrointestinal tract involves binding to albumin and transport of the zinc-albumin complex from intestine to liver (Hoadley and Cousins 1988). 

While unicellular fungi do not require metal transport systems, multi-cellular fungi and plants most certainly do, and we consider their transport in plants, and then consider how metal ions are sequestered in storage compartments before addressing their homeostasis. Once again, we consider in turn these processes for iron, copper and zinc. Since iron metabolism has been most intensively studied in S. cerevisiae, of all the fungi, we will focus our attention on iron homeostatic mechanisms, however, as the reader will see shortly, copper and zinc homeostasis have many similarities. 

In a manner similar to copper homeostasis, zinc homeostasis in mammals involves post-translational mechanisms. Both Zipl and Zip3 are found predominantly at the plasma... 

Outten CE, O Halloran TV (2001) Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science 292 2488-2492... 

Chimienti, F., Aouffen, M., Favier, A., and Seve, M. (2003). Zinc homeostasis-regulating proteins New drug targets for triggering cell fate. Curr. Drug Targets 4, 323-338. 

Concomitant expression of metallothioneins (MTs) and metalloproteinases (MMPs) occurs in skeletal muscle that has experienced an injury (Lecker et al. 2004 Warren et al. 2007). MTs are small (12-14 kDa), ubiquitous, cysteine-rich, zinc-binding proteins which are primarily produced in the liver and released into the circulation (Tapiero and Tew 2003). Upon release into the circulation these proteins play a pivotal role in cellular processes to render protection to all tissues of the body. In skeletal muscle, MTs initiate anti-inflammatory and anti-apoptotic signaling cascades, reduce reactive oxygen species (ROS)-induced cytotoxicity, protect against ROS-induced DNA degradation, and maintain zinc homeostasis... 

Researchers have proposed that metallothioneins possess multiple physiological functions including protection against metal toxicity, zinc homeostasis, and defense... 

The relative vulnerability of the secreted zinc to phytate complexatlon has only recently been demonstrated. The injection p zinc deficient rats intraperitoneally with a tracer dose of zlnc allows a portion of this zinc to be in equilibrium with the endogenous metabolic pool. This zinc then is secreted thru the saliva, pancreatic fluid, and bile. Those animals maintained on the phytate containing soy protein contained 2-4 times the radioactivity of the animals fed a casein protein diet (Table II). Therefore, not only does phytate affect the bioavailability of dietary zinc but also the reabsorption of endogenous zinc and thus has a net effect on zinc homeostasis. Since this total phytate effect cannot be measured ly labeling only the dietary pool, the expression of the net effect as the phytateizinc molar ratio is the most sensitive and accurate method of estimating the relative risk of zinc deficiency in any individual or population. 

In order to formulate a mechanism of action of phytate on zinc homeostasis, certain conditions must be fulfilled 1) The process must occur In the gastrointestinal tract since phytate Is not absorbed except for small amounts by birds 2) calcium must be a tertiary component in the total process but there must be some reaction without excessive amounts of calcium 3) certain chelating compounds such as EDTA must be capable of competing with the process and make some zinc available for absorption or reabsorption and 4) There must be some explanation for the data which indicates that 40% or more of the dietary pool may be available for absorption (, 49). All these conditions are satisfied by the following formula which is an expression of the "Law of Mass Action" ... 

Zinc homeostasis is largely regulated by its uptake and loss through the small intestine. Although a number of zinc transporters and binding proteins have been identified in villus epithehal cells, a full understanding of zinc absorption is not yet at hand. 

Takeda A, Minami A, Takefuta S, Tochigi M, Oku N (2001) Zinc homeostasis in the brain of adult rats fed zinc-deficient diet. J Neurosci Res 63 447-452 Taylor KM, Morgan HE, Johnson A, Hadley LJ, Nicholson R1 (2003) Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. Biochem J 375 51-59... 

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