Limits...
The Critical Roles of Zinc: Beyond Impact on Myocardial Signaling.

Lee SR, Noh SJ, Pronto JR, Jeong YJ, Kim HK, Song IS, Xu Z, Kwon HY, Kang SC, Sohn EH, Ko KS, Rhee BD, Kim N, Han J - Korean J. Physiol. Pharmacol. (2015)

Bottom Line: Whole body and cellular Zn(2+) levels are largely regulated by metallothioneins (MTs), Zn(2+) importers (ZIPs), and Zn(2+) transporters (ZnTs).However, these regulatory actions of Zn(2+) are not limited to the function of the heart, but also extend to numerous other organ systems, such as the central nervous system, immune system, cardiovascular tissue, and secretory glands, such as the pancreas, prostate, and mammary glands.In this review, the regulation of cellular Zn(2+) levels, Zn(2+)-mediated signal transduction, impacts of Zn(2+) on ion channels and mitochondrial metabolism, and finally, the implications of Zn(2+) in health and disease development were outlined to help widen the current understanding of the versatile and complex roles of Zn(2+).

View Article: PubMed Central - PubMed

Affiliation: Department of Integrated Biomedical Science, Cardiovascular and Metabolic disease Center, College of Medicine, Inje University, Busan 614-735, Korea.

ABSTRACT
Zinc has been considered as a vital constituent of proteins, including enzymes. Mobile reactive zinc (Zn(2+)) is the key form of zinc involved in signal transductions, which are mainly driven by its binding to proteins or the release of zinc from proteins, possibly via a redox switch. There has been growing evidence of zinc's critical role in cell signaling, due to its flexible coordination geometry and rapid shifts in protein conformation to perform biological reactions. The importance and complexity of Zn(2+) activity has been presumed to parallel the degree of calcium's participation in cellular processes. Whole body and cellular Zn(2+) levels are largely regulated by metallothioneins (MTs), Zn(2+) importers (ZIPs), and Zn(2+) transporters (ZnTs). Numerous proteins involved in signaling pathways, mitochondrial metabolism, and ion channels that play a pivotal role in controlling cardiac contractility are common targets of Zn(2+). However, these regulatory actions of Zn(2+) are not limited to the function of the heart, but also extend to numerous other organ systems, such as the central nervous system, immune system, cardiovascular tissue, and secretory glands, such as the pancreas, prostate, and mammary glands. In this review, the regulation of cellular Zn(2+) levels, Zn(2+)-mediated signal transduction, impacts of Zn(2+) on ion channels and mitochondrial metabolism, and finally, the implications of Zn(2+) in health and disease development were outlined to help widen the current understanding of the versatile and complex roles of Zn(2+).

No MeSH data available.


Impact of Zn2+ concentration on protein function in the cell. The total zinc concentration in a eukaryotic cell is relatively high (100~300 µM), but the actual amount of Zn2+ ranges from ~pM to ~nM values, depending on the cell type. Both extremely low and extremely high levels of Zn2+ have adverse effects on the cell. Excess Zn2+ causes irreversible effects on proteins, such as aggregation, which leads to the dysfunction of many proteins. Low levels of Zn2+ are also detrimental to the cell, since it is an important metal cofactor and signal transducer.
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Figure 1: Impact of Zn2+ concentration on protein function in the cell. The total zinc concentration in a eukaryotic cell is relatively high (100~300 µM), but the actual amount of Zn2+ ranges from ~pM to ~nM values, depending on the cell type. Both extremely low and extremely high levels of Zn2+ have adverse effects on the cell. Excess Zn2+ causes irreversible effects on proteins, such as aggregation, which leads to the dysfunction of many proteins. Low levels of Zn2+ are also detrimental to the cell, since it is an important metal cofactor and signal transducer.

Mentions: Zinc is the 24th most abundant element in the Earth's crust, with five naturally occurring isotopes. In 1869, scientists first described zinc as an essential nutrient for the growth of living organisms, due to the lack of its storage in major organs [1]. Zinc deficiency had been identified as a causative factor in the delayed sexual development and stunted growth in humans, because of the vital role of zinc in both male and female hormone production [2]. Normally, the human body contains 2~3 g of zinc (approx. 15.5 µM), 0.1% of which is exchanged daily [3]. Cellular zinc is most abundant in the cytoplasm (50%), followed by the nucleus (30~40%), and occurs least in the membrane (10%) [4]. Metalloproteomic analysis has revealed that prokaryotes use approximately 83% of their zinc proteins to carry out enzymatic catalysis, whereas eukaryotes utilize practically equal ratios of zinc-related proteins in catalytic reactions (47%) and DNA transcription (44%), while the remaining are involved in transport (5%) and signaling (3%) [5]. According to Costello et al., zinc occurring in mammalian biological systems can be classified into at least three forms, depending on its molecular behavior [6]: first, the non-exchangeable and non-reactive immobile zinc, which is tightly bound predominantly to proteins and comprises about 54% of the zinc pool; second, the "mobile reactive zinc" that is loosely bound to a ligand and is an exchangeable reactive pool of zinc (44.7%); and third, the reactive pool of zinc or the free zinc (<1%, ~5 pM~1 nM) (Fig. 1). Moreover, five types of Zn2+ sites are apparent from the examination of Zn2+-containing proteins: structural, multinuclear (clustered), catalytic (over 300 various enzymes), transport, and interprotein [789]. This reinforces the possibility of varied activities of zinc in cellular processes. Here, Zn2+ represents an exchangeable reactive pool and a reactive pool of zinc (or free zinc). The availability of Zn2+ inside the cell influences protein function, more evidently via interprotein Zn2+ binding sites, which responds to Zn2+ in a concentration-dependent manner [9]. Signaling cascades are induced not by non-exchangeable zinc (tightly bound to proteins), but by mobile reactive or free zinc.


The Critical Roles of Zinc: Beyond Impact on Myocardial Signaling.

Lee SR, Noh SJ, Pronto JR, Jeong YJ, Kim HK, Song IS, Xu Z, Kwon HY, Kang SC, Sohn EH, Ko KS, Rhee BD, Kim N, Han J - Korean J. Physiol. Pharmacol. (2015)

Impact of Zn2+ concentration on protein function in the cell. The total zinc concentration in a eukaryotic cell is relatively high (100~300 µM), but the actual amount of Zn2+ ranges from ~pM to ~nM values, depending on the cell type. Both extremely low and extremely high levels of Zn2+ have adverse effects on the cell. Excess Zn2+ causes irreversible effects on proteins, such as aggregation, which leads to the dysfunction of many proteins. Low levels of Zn2+ are also detrimental to the cell, since it is an important metal cofactor and signal transducer.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4553398&req=5

Figure 1: Impact of Zn2+ concentration on protein function in the cell. The total zinc concentration in a eukaryotic cell is relatively high (100~300 µM), but the actual amount of Zn2+ ranges from ~pM to ~nM values, depending on the cell type. Both extremely low and extremely high levels of Zn2+ have adverse effects on the cell. Excess Zn2+ causes irreversible effects on proteins, such as aggregation, which leads to the dysfunction of many proteins. Low levels of Zn2+ are also detrimental to the cell, since it is an important metal cofactor and signal transducer.
Mentions: Zinc is the 24th most abundant element in the Earth's crust, with five naturally occurring isotopes. In 1869, scientists first described zinc as an essential nutrient for the growth of living organisms, due to the lack of its storage in major organs [1]. Zinc deficiency had been identified as a causative factor in the delayed sexual development and stunted growth in humans, because of the vital role of zinc in both male and female hormone production [2]. Normally, the human body contains 2~3 g of zinc (approx. 15.5 µM), 0.1% of which is exchanged daily [3]. Cellular zinc is most abundant in the cytoplasm (50%), followed by the nucleus (30~40%), and occurs least in the membrane (10%) [4]. Metalloproteomic analysis has revealed that prokaryotes use approximately 83% of their zinc proteins to carry out enzymatic catalysis, whereas eukaryotes utilize practically equal ratios of zinc-related proteins in catalytic reactions (47%) and DNA transcription (44%), while the remaining are involved in transport (5%) and signaling (3%) [5]. According to Costello et al., zinc occurring in mammalian biological systems can be classified into at least three forms, depending on its molecular behavior [6]: first, the non-exchangeable and non-reactive immobile zinc, which is tightly bound predominantly to proteins and comprises about 54% of the zinc pool; second, the "mobile reactive zinc" that is loosely bound to a ligand and is an exchangeable reactive pool of zinc (44.7%); and third, the reactive pool of zinc or the free zinc (<1%, ~5 pM~1 nM) (Fig. 1). Moreover, five types of Zn2+ sites are apparent from the examination of Zn2+-containing proteins: structural, multinuclear (clustered), catalytic (over 300 various enzymes), transport, and interprotein [789]. This reinforces the possibility of varied activities of zinc in cellular processes. Here, Zn2+ represents an exchangeable reactive pool and a reactive pool of zinc (or free zinc). The availability of Zn2+ inside the cell influences protein function, more evidently via interprotein Zn2+ binding sites, which responds to Zn2+ in a concentration-dependent manner [9]. Signaling cascades are induced not by non-exchangeable zinc (tightly bound to proteins), but by mobile reactive or free zinc.

Bottom Line: Whole body and cellular Zn(2+) levels are largely regulated by metallothioneins (MTs), Zn(2+) importers (ZIPs), and Zn(2+) transporters (ZnTs).However, these regulatory actions of Zn(2+) are not limited to the function of the heart, but also extend to numerous other organ systems, such as the central nervous system, immune system, cardiovascular tissue, and secretory glands, such as the pancreas, prostate, and mammary glands.In this review, the regulation of cellular Zn(2+) levels, Zn(2+)-mediated signal transduction, impacts of Zn(2+) on ion channels and mitochondrial metabolism, and finally, the implications of Zn(2+) in health and disease development were outlined to help widen the current understanding of the versatile and complex roles of Zn(2+).

View Article: PubMed Central - PubMed

Affiliation: Department of Integrated Biomedical Science, Cardiovascular and Metabolic disease Center, College of Medicine, Inje University, Busan 614-735, Korea.

ABSTRACT
Zinc has been considered as a vital constituent of proteins, including enzymes. Mobile reactive zinc (Zn(2+)) is the key form of zinc involved in signal transductions, which are mainly driven by its binding to proteins or the release of zinc from proteins, possibly via a redox switch. There has been growing evidence of zinc's critical role in cell signaling, due to its flexible coordination geometry and rapid shifts in protein conformation to perform biological reactions. The importance and complexity of Zn(2+) activity has been presumed to parallel the degree of calcium's participation in cellular processes. Whole body and cellular Zn(2+) levels are largely regulated by metallothioneins (MTs), Zn(2+) importers (ZIPs), and Zn(2+) transporters (ZnTs). Numerous proteins involved in signaling pathways, mitochondrial metabolism, and ion channels that play a pivotal role in controlling cardiac contractility are common targets of Zn(2+). However, these regulatory actions of Zn(2+) are not limited to the function of the heart, but also extend to numerous other organ systems, such as the central nervous system, immune system, cardiovascular tissue, and secretory glands, such as the pancreas, prostate, and mammary glands. In this review, the regulation of cellular Zn(2+) levels, Zn(2+)-mediated signal transduction, impacts of Zn(2+) on ion channels and mitochondrial metabolism, and finally, the implications of Zn(2+) in health and disease development were outlined to help widen the current understanding of the versatile and complex roles of Zn(2+).

No MeSH data available.