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Cuajungco, M.P. Zinc and Health. Encyclopedia. Available online: https://encyclopedia.pub/entry/8064 (accessed on 18 May 2024).
Cuajungco MP. Zinc and Health. Encyclopedia. Available at: https://encyclopedia.pub/entry/8064. Accessed May 18, 2024.
Cuajungco, Math P.. "Zinc and Health" Encyclopedia, https://encyclopedia.pub/entry/8064 (accessed May 18, 2024).
Cuajungco, M.P. (2021, March 17). Zinc and Health. In Encyclopedia. https://encyclopedia.pub/entry/8064
Cuajungco, Math P.. "Zinc and Health." Encyclopedia. Web. 17 March, 2021.
Zinc and Health
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines9020208

Zinc is a redox-inert trace element that is second only to iron in abundance in biological systems. In cells, zinc is typically buffered and bound to metalloproteins, but it may also exist in a labile or chelatable (free ion) form. Zinc plays a critical role in prokaryotes and eukaryotes, ranging from structural to catalytic to replication to demise. 

metalloproteins zinc transporters metal chelators antibiotic resistance antimicrobials

1. Introduction

Zinc, an essential component of life in the three domains, follows iron as the second most abundant transition metal ion in living organisms [1][2]. About 5–6% and 9–10% of proteins from prokaryotes and eukaryotes, respectively, depend on this metal to fulfill their biological functions [1]. A bioinformatics study found that over 50% of zinc-bound proteins are enzymes, and in the vast majority of them, the metal plays a catalytic role [3]. About 20% of them use zinc as a structural component, and in a small percentage, it is a regulator or substrate of enzymatic activity [3][4][5]. The requirement of zinc in such a high number of proteins illustrates its fundamental role in numerous biological processes [6][7][8][9][10][11]. The essential nature of zinc for cellular viability, together with the toxic nature of the element in higher concentrations, led prokaryotes [12] and eukaryotes [13] to evolve export and import systems to keep ionic homeostasis.

2. Prokaryotes

2.1. Zinc as Antimicrobial

Zinc is a member of the group of metals that participate in the nonspecific mechanisms of defense against infection [14][15]. The host defenses reduce trace elements’ availability to starve the infecting bacterial cells in a response known as “nutritional immunity”, a term coined in the mid-70s [16]. The first hint to this defense strategy’s existence occurred in the mid-40s, when the high-affinity iron-binding transferrin was discovered [17][18]. Immediately after the invasion of infecting bacteria, the body responds, reducing free iron levels in the blood and tissue (hypoferremic response) [19][20]. Posterior studies have shown that nutritional immunity is a strategy that is not limited to iron sequestration and also includes restricting the availability of other essential elements, including zinc [21][22][23][24][25]. In the face of these nutritional limitations, microorganisms evolved stratagems to scavenge sufficient quantities of trace elements necessary to support their metabolism and growth. Zinc is a component of nutritional immunity; in human serum, which contains 0.1% of the total body zinc, about 98% is bound to proteins, mainly albumin (80–85%) and alpha-2-macroglobulin (5–15%), and in marginal quantities to other proteins [26][27][28]. Additionally, zinc is further restricted to pathogens in ongoing infections by releasing calprotectin, a protein that sequesters this metal and creates zinc-limited microenvironments [29][30][31][32]. Calprotectin, a heterodimer formed by the S100A8 and S100A9 proteins, also binds manganese and iron [31][33][34], and it has a proven effect against infection [23][33][34][35][36][37][38]. Other proteins, like the S100 family calgranulin C (S100A12) and psoriasin (S100A7), have also been shown to be able to bind zinc and could contribute to nutritional immunity response [39][40]. As zinc is a component of nutritional immunity, bacteria need to sense the intracellular concentrations and put in motion the different mechanisms involved in this element’s homeostasis. Interestingly, while essential to support growth, zinc is also known to inhibit the progress of infectious processes caused by bacteria [41][42] and viruses, including SARS-CoV-2, the causative agent of COVID-19 [43][44][45][46]. Zinc also inhibits SOS-induced antibiotic resistance and horizontal transfer of antibiotic resistance genes in enteric bacteria [47][48]. Another utilization of zinc as defense by the human host is through macrophages, which use it within the phagolysosome to intoxicate invading bacterial cells [49][50][51][52][53]. A common mechanism by which zinc in excess is toxic to bacterial cells is by binding to noncognate proteins [52][54][55][56].

The effect of zinc in the progress of infection was also investigated utilizing zinc-deficient murine models [45][57][58]. Furthermore, zinc-deficient mice were found to be suitable models for more general studies of infections caused by enterotoxigenic Escherichia coli, Shigella flexneri, and Campylobacter jejuni and potential treatments and immunization [45][57][58].

While zinc uptake is an essential process for bacterial pathogens to cause disease, this element can also be detrimental to some infections. Since long ago, zinc has been used as treatment and prophylaxis of diarrheal diseases [59][60][61]. It was originally thought that the beneficial effect of zinc in treating enteropathogenic E. coli (EPEC)-produced diarrhea was entirely caused by enhancement of the immune response and inhibition of ecto-5’-nucleotidase, an enzyme that catalyzes the conversion of the 5’-AMP to the secretagogue adenosine [57][58]. However, this initial idea proved to be insufficient to explain the therapeutic effects observed [57][58][62]. Addition of zinc acetate at sublethal concentrations caused a decrease in the expression of various virulence factors [62]. The mRNA species corresponding to the bfp gene (bindle forming protein) and various esp genes (EPEC-secreted proteins) were expressed at reduced levels. Furthermore, zinc acetate lowered the bacterial cells’ adherence, inhibited secretion of infection-induced fluids into ileal loops, and reduced histopathological damage in an animal model of infection [62]. Zinc acetate also had effects on the virulence of Shiga-toxigenic E. coli (STEC) and enteroaggregative E. coli (EAEC) [44][45][63]. It inhibited STEC adherence to cultured cells, expression of enterohemorrhagic E. coli (EHEC)-secreted protein A (EspA) and Shiga toxin. In vivo, it reduced fluid secretion and toxin levels in the loops and reduced STEC-induced histological damage [64]. In several forms like oxide, sulfate, and acetate, zinc was also used to test its effects on EAEC [42]. A decrease was observed in biofilm formation, cell adhesion, and expression of other potential or confirmed virulence factors [42]. The observation that zinc reduced the expression of recA suggests that inhibition of the SOS response may be one mechanism by which zinc acts on E. coli virulence [41]. This finding also prompted other studies to test if zinc could also reduce SOS-induced hypermutation response to antibiotics or horizontal transfer of resistance traits [48][65][66][67]. Zinc blocked the SOS-induced (hypermutation response) development of resistance in E. coli, Klebsiella pneumoniae, and Enterobacter cloacae, probably by inhibiting RecA binding to single-stranded DNA [47]. Zinc also interfered with horizontal transfer of a β-lactamase gene from Enterobacter to E. coli strain [47]. As observed with other zinc effects [63][68], the complex zinc ionophore showed significantly higher activity than zinc salts in inhibition antibiotic-induced hypermutation [47].

Environmental enteropathy, a small intestinal disorder caused by subclinical intestinal infections, produces chronic low-grade intestinal inflammation and dysregulation of tight junctions [69][70]. A study on adults with environmental enteropathy showed disruptions that cause leakage in the patients’ epithelial barrier [69]. The authors hypothesized that the sites with epithelial defects could be responsible for bacterial translocation. In vitro experiments utilizing enteropathogenic E. coli and Citrobacter rodentium showed that these bacteria induced barrier dysfunction, and treatment with numerous compounds like zinc, epidermal growth factor, colostrum, trefoil factor 3, resistin-like molecule-β, hydrocortisone, and ML7 (an inhibitor of the myosin light chain kinase) increased transepithelial resistance while reducing bacterial translocation [71]. This effect was nutrient-independent, and, of all the tested compounds, only zinc exhibited an antimicrobial activity [71].

2.2. Zinc Oxide Nanoparticles as Antibacterial

Zinc ions at concentrations higher than those needed for the cells’ normal physiology are detrimental [12]. Multiple effects of excess zinc concentrations lead to bacterial cell death [12][52]. Interestingly, zinc ions at sublethal concentrations inhibit biofilm formation but do not disrupt preformed biofilms in Actinobacillus pleuropneumoniae, Salmonella typhimurium, Haemophilus parasuis, and at a lesser level, E. coli, Staphylococcus aureus, and Streptococcus suis [72]. Zinc oxide is the most common, but not the only, zinc compound used as an antibacterial [73][74], and it has attracted great interest in nanoparticle form [75][76]. Zinc oxide nanoparticles are being researched for applications not only against infections but also as drug delivery tools and as therapies for a variety of conditions [75]. The enthusiasm for nanoparticles’ uses as antibacterial agents is partly fueled by their particular mechanisms of action that differ from those utilized by currently used antibiotics and have targets reducing the frequency of appearance of resistant strains [77][78]. Various research teams have tested the activity of zinc oxide nanoparticles as antibacterials against numerous species [75][76][79][80][81][82][83][84]. The mechanism by which zinc is toxic to bacterial cells is ultimately that of other forms of the ion; however, zinc oxide seems to be more effective when it is administered in nanoparticle form [80][81][85]. Zinc oxide nanoparticles release zinc in an aqueous medium, which then penetrates the cells and produces toxic effects [75]. Zinc oxide nanoparticles are robust candidates to be developed as standalone antimicrobials or as components in combination therapies against multiresistant bacterial infections.

3. Eukaryotes

3.1. Importance of Zinc in Eukaryotic Cells

The effectiveness of antibiotics against bacteria exemplifies the importance of these drugs against many human infections. Unfortunately, the same drugs that kill bacteria have similar effects on the mitochondria present within eukaryotic cells [86]. The synergistic effect of zinc with antibiotics may also be the reason why zinc itself is toxic to eukaryotic cells at high intracellular levels because zinc enters the mitochondria and enhances production of reactive oxygen species (ROS) [87][88].

In eukaryotic cells, zinc exists in labile or free ion form (chelatable) [89], while zinc bound to proteins serve in a structural or catalytic capacity [89][90][91]. Zinc is a small ion (~0.65 angstrom) that binds nitrogen- and sulfur-containing molecules and readily exchanges ligands due to its low ligand field stabilization energy. Intracellular zinc levels range from 10−12 to 10−9 M in most cells, but zinc-enriched cells such as neurons, hepatocytes, splenocytes, and thymocytes may contain an estimated 10−6 to 10−5 M amount [92][93][94][95]. Zinc concentrations range from 10−9 M within the cytoplasm in most cells to 10−3 M in some vesicles [96]. In transgenic baby hamster kidney cells that express zinc influx transporter proteins, Palmiter and colleagues (1996) estimated that vesicular zinc concentrations reach 14 µM when these cells are exposed to high levels of exogenous zinc [97]. Cell survival in vitro is compromised when cells are exposed to extracellular zinc concentrations ([Zn2+]e) between 225–1000 µM in neuronal cells and 7.5–200 µM in non-neuronal cells [98][99][100][101]. It is therefore essential that cells regulate their intracellular zinc concentrations through protein influxers and effluxers as well as physiological chelation by apo-thionein or other zinc-sequestering apoproteins [97][102][103][104][105].

3.2. Zinc-Rich Cells

Zinc-rich cells in mammals are found in various tissue and organs, particularly in the brain, mammary gland, intestine, pancreas, thymus, prostate gland, testes, and ovaries [89][106][107][108]. In the brain, high levels of chelatable or labile zinc is synaptically co-released with glutamate during normal neuronal communication [89], with ionic levels reaching 100–300 µM, particularly during a seizure activity [109][110]. Intracellular zinc is typically buffered but is exocytosed from neurons or secretory cells that release vesicles or granules, respectively. Zinc release in the hippocampal mossy fiber terminals is calcium-dependent whether it was evoked via potassium or kainic acid administration and spontaneous activity [109][111][112][113]. Intracellular zinc elevation may occur due to high exogenous zinc levels [114][115][116][117][118] or caused by cytoplasmic zinc release from compartments or proteins due to oxidation by ROS or nitrosylation by reactive nitrogen species [119][120][121]. Zinc overload kills neurons, and thus it is imperative that cells tightly regulate intracellular zinc concentration via zinc transporters and buffering of zinc-binding amino acids or proteins.

3.3. Zinc Transporters

High- and low-affinity uptake mechanisms for zinc have been identified with dissociation constants (Kd) of 15 and 361 µM, respectively [109]. An even higher binding affinity constant (Ka) of 0.25 µM has been reported for zinc, which is saturable, ATP-independent, and unaffected by Na+ concentration gradient [122]. Indeed, zinc levels are strictly maintained by tissue-specific and highly conserved low molecular weight transport protein families known as the ZnTs (also known as SLC30 for solute carrier 30) and ZIPs (also known as SLC39 for solute carrier 39) [123][124][125]. Early studies in the field led to the discovery of mammalian ZnTs involved in the extrusion of zinc out of cells named ZnT1 [102] and sequestration of zinc into compartments called ZnT2 [97]. ZnT1 is mainly localized in the plasma membrane [102]. Meanwhile, ZnT2 is localized within vesicular (acidic) compartments, such as lysosomes, but has a low affinity for zinc [97]. Another effluxer termed ZnT3 was cloned and identified to localize within synaptic vesicles of zinc-rich neurons [104]. ZnT3 is expressed in the mammalian brain, such as in the cerebral cortex and the hippocampus, and strongly detected in the dentate granule cells. Over the course of time, other members of the ZnT effluxers (ZnT4–ZnT10) and ZIP influxers (ZIP1–ZIP14) were identified through sequence similarity analyses, cloning, and functional experimentations [110][125]. More recently, transmembrane 163 protein (TMEM163; also known as SV31) [126][127] was functionally characterized as a dimeric protein that effluxes zinc [128], and one of us proposed that TMEM163 be now classified as ZnT11 as a new member of the ZnT efflux family of proteins [128]. One commonality among ZIPs and ZnTs is that histidine (H) and/or aspartic acid (D) residues, such as the HXXXD motif (where X is a nonpolar amino acid) typically located within transmembrane domain (TMD)-4 and TMD5 helices of ZIPs, as well as HXXXH motif found in TMD2 and TM5 helices of ZnTs have been shown to be responsible for tetrahedral zinc coordination [110][129]. For a relevant review on certain zinc transporters, we refer the reader to the paper by Styrpejko and Cuajungco (2021) as part of this Special Issue.

In addition to transporters, intracellular buffers offer a secondary defense mechanism to prevent intracellular zinc overload, such as the metallothioneins (MTs)—a group of low molecular weight (~6–7 kDa), single polypeptide chains with four functional mammalian isoforms (MT1−MT4) [106][130]. MTs, however, are not a long-term storage for zinc due to its short biological half-life [131]. Thus, vesicular or compartmental storage mediated by ZnTs and ZIPs provide important contributions to zinc homeostasis.

References

  1. Andreini, I.; Banci, C.L.; Bertini, I.; Rosato, A. Zinc through the three domains of life. J. Proteome Res. 2006, 5, 3173–3178.
  2. Maxfield, L.; Crane, J.S. Zinc Deficiency; StatPearls: Treasure Island, FL, USA, 2020.
  3. Andreini, C.; Bertini, I. A bioinformatics view of zinc enzymes. J. Inorg. Biochem. 2012, 111, 150–156.
  4. Banci, L.; Bertini, I.; Ciofi-Baffoni, S.; Finney, L.A.; Outten, C.E.; O’Halloran, T.V. A new zinc-protein coordination site in intracellular metal Trafficking: Solution structure of the Apo and Zn(II) forms of ZntA(46–118). J. Mol. Biol. 2002, 323, 883–897.
  5. Debela, M.; Magdolen, V.; Grimminger, V.; Sommerhoff, C.; Messerschmidt, A.; Huber, R.; Friedrich, R.; Bode, W.; Goettig, P. Crystal structures of human tissue kallikrein 4: Activity modulation by a specific zinc binding site. J. Mol. Biol. 2006, 362, 1094–1107.
  6. Mikhaylina, A.; Ksibe, A.Z.; Scanlan, D.J.; Blindauer, C.A. Bacterial zinc uptake regulator proteins and their regulons. Biochem. Soc. Trans. 2018, 46, 983–1001.
  7. Coleman, J.E. Zinc proteins: Enzymes, storage proteins, transcription factors, and replication proteins. Annu. Rev. Biochem. 1992, 61, 897–946.
  8. Loh, S.N. The missing Zinc: p53 misfolding and cancer. Metallomics 2010, 2, 442–449.
  9. Namuswe, F.; Berg, J.M. Secondary interactions involving zinc-bound ligands: Roles in structural stabilization and macromolecular interactions. J. Inorg. Biochem. 2012, 111, 146–149.
  10. Eriksson, S.E.; Ceder, S.; Bykov, V.J.N.; Wiman, K.G. p53 as a hub in cellular redox regulation and therapeutic target in cancer. J. Mol. Cell Biol. 2019, 11, 330–341.
  11. Buberg, M.L.; Witsø, I.L.; L’Abée-Lund, T.M.; Wasteson, Y. Zinc and Copper Reduce Conjugative Transfer of Resistance Plasmids from Extended-Spectrum Beta-Lactamase-Producing Escherichia coli. Microb. Drug Resist. 2020, 26, 842–849.
  12. Blencowe, D.K.; Morby, A.P. Zn(II) metabolism in prokaryotes. FEMS Microbiol. Rev. 2003, 27, 291–311.
  13. Eide, D. Molecular biology of iron and zinc uptake in eukaryotes. Curr. Opin. Cell Biol. 1997, 9, 573–577.
  14. Hennigar, S.R.; McClung, J.P. Nutritional immunity: Starving pathogens of trace minerals. Am. J. Lifestyle Med. 2016, 10, 170–173.
  15. Wooldridge, K.G.; Williams, P.H. Iron uptake mechanisms of pathogenic bacteria. FEMS Microbiol. Rev. 1993, 12, 325–348.
  16. Weinberg, E.D. Nutritional immunity. Host’s attempt to withold iron from microbial invaders. JAMA 1975, 231, 39–41.
  17. Schade, A.L.; Caroline, L. Raw hen egg white and the role of iron in growth inhibition of Shigella dysenteriae, Staphylococcus aureus, Escherichia coli and Saccharomyces cerevisiae. Science 1944, 100, 14–15.
  18. Schade, A.L.; Caroline, L. An Iron-binding Component in Human Blood Plasma. Science 1946, 104, 340–341.
  19. Weinberg, E.D. Iron withholding: A defense against infection and neoplasia. Physiol. Rev. 1984, 64, 65–102.
  20. Weinberg, E.D. Iron depletion: A defense against intracellular infection and neoplasia. Life Sci. 1992, 50, 1289–1297.
  21. Kehl-Fie, T.E.; Skaar, E.P. Nutritional immunity beyond iron: A role for manganese and zinc. Curr. Opin. Chem. Biol. 2010, 14, 218–224.
  22. Corbin, B.D.; Seeley, E.H.; Raab, A.; Feldmann, J.; Miller, M.R.; Torres, V.J.; Anderson, K.L.; Dattilo, B.M.; Dunman, P.M.; Gerads, R.; et al. Metal chelation and inhibition of bacterial growth in tissue abscesses. Science 2008, 319, 962–965.
  23. Hood, M.I.; Mortensen, B.L.; Moore, J.L.; Zhang, Y.; Kehl-Fie, T.E.; Sugitani, N.; Chazin, W.J.; Caprioli, R.M.; Skaar, E.P. Identification of an Acinetobacter baumannii zinc acquisition system that facilitates resistance to calprotectin-mediated zinc sequestration. PLoS Pathog. 2012, 8, e1003068.
  24. Hood, M.I.; Skaar, E.P. Nutritional immunity: Transition metals at the pathogen–host interface. Nat. Rev. Genet. 2012, 10, 525–537.
  25. Lonergan, Z.R.; Skaar, E.P. Nutrient Zinc at the Host–Pathogen Interface. Trends Biochem. Sci. 2019, 44, 1041–1056.
  26. Craig, G.M.; Evans, S.J.; Brayshaw, B.J.; Raina, S.K. A study of serum zinc, albumin, alpha-2-macroglobulin and transferrin levels in acute and long stay elderly hospital patients. Postgrad. Med. J. 1990, 66, 205–209.
  27. Foote, J.W.; Delves, H.T. Albumin bound and alpha 2-macroglobulin bound zinc concentrations in the sera of healthy adults. J. Clin. Pathol. 1984, 37, 1050–1054.
  28. Foote, J.W.; Delves, H.T. Distribution of zinc amongst human serum globulins determined by gel filtration-affinity chromatography and atomic-absorption spectrophotometry. Analyst 1984, 109, 709–711.
  29. Zygiel, E.M.; Nolan, E.M. Transition Metal Sequestration by the Host-Defense Protein Calprotectin. Annu. Rev. Biochem. 2018, 87, 621–643.
  30. Damo, S.M.; Kehl-Fie, T.E.; Sugitani, N.; Holt, M.E.; Rathi, S.; Murphy, W.J.; Zhang, Y.; Betz, C.; Hench, L.; Günter, F.; et al. Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens. Proc. Natl. Acad. Sci. USA 2013, 110, 3841–3846.
  31. Nakashige, T.G.; Stephan, J.R.; Cunden, L.S.; Brophy, M.B.; Wommack, A.J.; Keegan, B.C.; Shearer, J.M.; Nolan, E.M. The hexahistidine motif of host-defense protein human calprotectin contributes to zinc withholding and its functional versatility. J. Am. Chem. Soc. 2016, 138, 12243–12251.
  32. Stephan, J.R.; Nolan, E.M. Calcium-induced tetramerization and zinc chelation shield human calprotectin from degradation by host and bacterial extracellular proteases. Chem. Sci. 2016, 7, 1962–1975.
  33. Sohnle, P.G.; Collins-Lech, C.; Wiessner, J.H. The Zinc-Reversible Antimicrobial Activity of Neutrophil Lysates and Abscess Fluid Supernatants. J. Infect. Dis. 1991, 164, 137–142.
  34. Sohnle, P.G.; Collins-Lech, C.; Wiessner, J.H. Antimicrobial Activity of an Abundant Calcium-Binding Protein in the Cytoplasm of Human Neutrophils. J. Infect. Dis. 1991, 163, 187–192.
  35. Steinbakk, M.; Naess-Andresen, C.F.; Lingaas, E.; Dale, I.; Brandtzaeg, P.; Fagerhol, M.K. Antimicrobial actions of calcium binding leucocyte L1 protein, calprotectin. Lancet 1990, 336, 763–765.
  36. Haase, H.; Rink, L. Multiple impacts of zinc on immune function. Metallomics 2014, 6, 1175–1180.
  37. Haase, H.; Rink, L. Zinc signals and immune function. BioFactors 2014, 40, 27–40.
  38. Achouiti, A.; Vogl, T.; Urban, C.F.; Rohm, M.; Hommes, T.J.; van Zoelen, M.A.; Florquin, S.; Roth, J.; van ’t Veer, C.; de Vos, A.F.; et al. Myeloid-related protein-14 contributes to protective immunity in gram-negative pneumonia derived sepsis. PLoS Pathog. 2012, 8, e1002987.
  39. Lopez, C.A.; Beavers, W.N.; Weiss, A.; Knippel, R.J.; Zackular, J.P.; Chazin, W.; Skaar, E.P. The immune protein calprotectin impacts Clostridioides difficile metabolism through zinc limitation. MBio 2019, 10, e02289–e19.
  40. Cunden, L.S.; Brophy, M.B.; Rodriguez, G.E.; Flaxman, H.A.; Nolan, E.M. Biochemical and functional evaluation of the intramolecular disulfide bonds in the zinc-chelating antimicrobial protein human S100A7 (psoriasin). Biochemistry 2017, 56, 5726–5738.
  41. Crane, J.K.; Broome, J.E.; Reddinger, R.M.; Werth, B.B. Zinc protects against Shiga-toxigenic Escherichia coli by acting on host tissues as well as on bacteria. BMC Microbiol. 2014, 14, 145.
  42. Medeiros, P.; Bolick, D.T.; Roche, J.K.; Noronha, F.; Pinheiro, C.; Kolling, G.L.; Lima, A.; Guerrant, R.L. The micronutrient zinc inhibits EAEC strain 042 adherence, biofilm formation, virulence gene expression, and epithelial cytokine responses benefiting the infected host. Virulence 2013, 4, 624–633.
  43. Hunter, J.; Arentz, S.; Goldenberg, J.; Yang, G.; Beardsley, J.; Mertz, D.; Leeder, S. Rapid review protocol: Zinc for the prevention or treatment of COVID-19 and other coronavirus-related respiratory tract infections. Integr. Med. Res. 2020, 9, 100457.
  44. te Velthuis, A.J.; van den Worm, S.H.; Sims, A.C.; Baric, R.S.; Snijder, E.J.; van Hemert, M.J. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010, 6, e1001176.
  45. Cordingley, M.G.; Register, R.B.; Callahan, P.L.; Garsky, V.M.; Colonno, R.J. Cleavage of small peptides in vitro by human rhinovirus 14 3C protease expressed in Escherichia coli. J. Virol. 1989, 63, 5037–5045.
  46. Fenstermacher, K.J.; DeStefano, J.J. Mechanism of HIV reverse transcriptase inhibition by zinc: Formation of a highly stable enzyme-(primer-template) complex with profoundly diminished catalytic activity. J. Biol. Chem. 2011, 286, 40433–40442.
  47. Crane, J.K.; Cheema, M.B.; Olyer, M.A.; Sutton, M.D. Zinc blockade of SOS response inhibits horizontal transfer of antibiotic resistance genes in enteric bacteria. Front. Cell Infect. Microbiol. 2018, 8, 410.
  48. Bunnell, B.E.; Escobar, J.F.; Bair, K.L.; Sutton, M.D.; Crane, J.K. Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli. PLoS ONE 2017, 12, e0178303.
  49. Botella, H.; Peyron, P.; Levillain, F.; Poincloux, R.; Poquet, Y.; Brandli, I.; Wang, C.; Tailleux, L.; Tilleul, S.; Charriere, G.M.; et al. Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages. Cell Host Microbe. 2011, 10, 248–259.
  50. Ong, C.L.; Gillen, C.M.; Barnett, T.C.; Walker, M.J.; McEwan, A.G. An antimicrobial role for zinc in innate immune defense against group A streptococcus. J. Infect. Dis. 2014, 209, 1500–1508.
  51. Kapetanovic, R.; Bokil, N.J.; Achard, M.E.; Ong, C.L.; Peters, K.M.; Stocks, C.J.; Phan, M.D.; Monteleone, M.; Schroder, K.; Irvine, K.M.; et al. Salmonella employs multiple mechanisms to subvert the TLR-inducible zinc-mediated antimicrobial response of human macrophages. FASEB J. 2016, 30, 1901–1912.
  52. McDevitt, C.A.; Ogunniyi, A.D.; Valkov, E.; Lawrence, M.C.; Kobe, B.; McEwan, A.G.; Paton, J.C. A molecular mechanism for bacterial susceptibility to zinc. PLoS Pathog. 2011, 7, e1002357.
  53. Botella, H.; Stadthagen, G.; Lugo-Villarino, G.; De Chastellier, C.; Neyrolles, O. Metallobiology of host–pathogen interactions: An intoxicating new insight. Trends Microbiol. 2012, 20, 106–112.
  54. Eijkelkamp, B.A.; Morey, J.R.; Ween, M.P.; Ong, C.L.; McEwan, A.G.; Paton, J.C.; McDevitt, C.A. Extracellular zinc competitively inhibits manganese uptake and compromises oxidative stress management in Streptococcus pneumoniae. PLoS ONE 2014, 9, e89427.
  55. Ong, C.-L.Y.; Walker, M.J.; McEwan, A.G. Zinc disrupts central carbon metabolism and capsule biosynthesis in Streptococcus pyogenes. Sci. Rep. 2015, 5, 10799.
  56. Makthal, N.; Kumaraswami, M. Zinc’ing it out: Zinc homeostasis mechanisms and their impact on the pathogenesis of human pathogen group A streptococcus. Metallomics 2017, 9, 1693–1702.
  57. Crane, J.K.; Olson, R.A.; Jones, H.M.; Duffey, M.E. Release of ATP during host cell killing by enteropathogenic E. coli and its role as a secretory mediator. Am. J. Physiol. Gastrointest. Liver Physiol. 2002, 283, G74–G86.
  58. Crane, J.K.; Shulgina, I.; Naeher, T.M. Ecto-5′-nucleotidase and intestinal ion secretion by enteropathogenic Escherichia coli. Purinergic Signal. 2007, 3, 233–246.
  59. Barffour, M.A.; Hinnouho, G.M.; Wessells, K.R.; Kounnavong, S.; Ratsavong, K.; Sitthideth, D.; Bounheuang, B.; Sengnam, K.; Chanhthavong, B.; Arnold, C.D.; et al. Effects of therapeutic zinc supplementation for diarrhea and two preventive zinc supplementation regimens on the incidence and duration of diarrhea and acute respiratory tract infections in rural Laotian children: A randomized controlled trial. J. Glob. Health 2020, 10, 010424.
  60. Bhutta, Z.A.; Bird, S.M.; Black, R.E.; Brown, K.H.; Gardner, J.M.; Hidayat, A.; Khatun, F.; Martorell, R.; Ninh, N.X.; Penny, M.E.; et al. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: Pooled analysis of randomized controlled trials. Am. J. Clin. Nutr. 2000, 72, 1516–1522.
  61. Metzler-Zebeli, B.U.; Caine, W.R.; McFall, M.; Miller, B.; Ward, T.L.; Kirkwood, R.N.; Mosenthin, R. Supplementation of diets for lactating sows with zinc amino acid complex and gastric nutriment-intubation of suckling pigs with zinc methionine on mineral status, intestinal morphology and bacterial translocation in lipopolysaccharide-challenged weaned pigs. J. Anim. Physiol. Anim. Nutr. (Berl) 2010, 94, 237–249.
  62. Crane, J.K.; Naeher, T.M.; Shulgina, I.; Zhu, C.; Boedeker, E.C. Effect of zinc in enteropathogenic Escherichia coli infection. Infect. Immun. 2007, 75, 5974–5984.
  63. Magallon, J.; Chiem, K.; Tran, T.; Ramirez, M.S.; Jimenez, V.; Tolmasky, M.E. Restoration of susceptibility to amikacin by 8-hydroxyquinoline analogs complexed to zinc. PLoS ONE 2019, 14, e0217602.
  64. Crane, J.K.; Byrd, I.W.; Boedeker, E.C. Virulence Inhibition by Zinc in Shiga-ToxigenicEscherichia coli. Infect. Immun. 2011, 79, 1696–1705.
  65. Cirz, R.T.; Romesberg, F.E. Induction and Inhibition of Ciprofloxacin Resistance-Conferring Mutations in Hypermutator Bacteria. Antimicrob. Agents Chemother. 2006, 50, 220–225.
  66. Recacha, E.; Machuca, J.; De Alba, P.D.; Ramos-Güelfo, M.; Pérez, F.M.D.; Beltrán, J.R.; Blázquez, J.; Pascual, A.; Martínez, J.M.R. Quinolone Resistance Reversion by Targeting the SOS Response. MBio 2017, 8, e00971-17.
  67. Plaut, R.D.; Beaber, J.W.; Zemansky, J.; Kaur, A.P.; George, M.; Biswas, B.; Henry, M.; Bishop-Lilly, K.A.; Mokashi, V.; Hannah, R.M.; et al. Genetic evidence for the involvement of the S-layer protein gene sap and the sporulation genes spo0A, spo0B, and spo0F in phage AP50c infection of Bacillus anthracis. J. Bacteriol. 2014, 196, 1143–1154.
  68. Lin, D.L.; Tran, T.; Alam, J.Y.; Herron, S.R.; Ramirez, M.S.; Tolmasky, M.E. Inhibition of aminoglycoside 6’-N-acetyltransferase type Ib by zinc: Reversal of amikacin resistance in Acinetobacter baumannii and Escherichia coli by a zinc ionophore. Antimicrob. Agents Chemother. 2014, 58, 4238–4241.
  69. Kelly, P.; Besa, E.; Zyambo, K.; Louis-Auguste, J.; Lees, J.; Banda, T.; Soko, R.; Banda, R.; Amadi, B.; Watson, A. Endomicroscopic and transcriptomic analysis of impaired barrier function and Mmalabsorption in environmental enteropathy. PLoS Negl. Trop. Dis. 2016, 10, e0004600.
  70. Korpe, P.S.; Petri, W.A., Jr. Environmental enteropathy: Critical implications of a poorly understood condition. Trends Mol. Med. 2012, 18, 328–336.
  71. Choudhry, N.; Scott, F.; Edgar, M.; Sanger, G.J.; Kelly, P. Reversal of pathogen-induced barrier defects in intestinal epithelial cells by contra-pathogenicity agents. Dig. Dis. Sci. 2021, 66, 88–104.
  72. Wu, C.; Labrie, J.; Tremblay, Y.D.; Haine, D.; Mourez, M.; Jacques, M. Zinc as an agent for the prevention of biofilm formation by pathogenic bacteria. J. Appl. Microbiol. 2013, 115, 30–40.
  73. Kolodziejczak-Radzimska, A.; Jesionowski, T. Zinc oxide-from synthesis to application: A review. Materials 2014, 7, 2833–2881.
  74. Morshedtalab, Z.; Rahimi, G.; Emami-Nejad, A.; Farasat, A.; Mohammadbeygi, A.; Ghaedamini, N.; Negahdary, M. Antibacterial assessment of zinc sulfide nanoparticles against Streptococcus pyogenes and Acinetobacter baumannii. Curr. Top Med. Chem. 2020, 20, 1042–1055.
  75. Sanchez-Lopez, E.; Gomes, D.; Esteruelas, G.; Bonilla, L.; Lopez-Machado, A.L.; Galindo, R.; Cano, A.; Espina, M.; Ettcheto, M.; Camins, A.; et al. Metal-based nanoparticles as antimicrobial agents: An overview. NanoMaterials 2020, 10, 292.
  76. Ye, Q.; Chen, W.; Huang, H.; Tang, Y.; Wang, W.; Meng, F.; Wang, H.; Zheng, Y. Iron and zinc ions, potent weapons against multidrug-resistant bacteria. Appl. Microbiol. Biotechnol. 2020, 104, 5213–5227.
  77. Slavin, Y.N.; Asnis, J.; Hafeli, U.O.; Bach, H. Metal nanoparticles: Understanding the mechanisms behind antibacterial activity. J. Nanobiotechnol. 2017, 15, 65.
  78. Stensberg, M.C.; Wei, Q.; McLamore, E.S.; Porterfield, D.M.; Wei, A.; Sepulveda, M.S. Toxicological studies on silver nanoparticles: Challenges and opportunities in assessment, monitoring and imaging. Nanomedicine (Lond) 2011, 6, 879–898.
  79. Vijayakumar, S.; Krishnakumar, C.; Arulmozhi, P.; Mahadevan, S.; Parameswari, N. Biosynthesis, characterization and antimicrobial activities of zinc oxide nanoparticles from leaf extract of Glycosmis pentaphylla (Retz.) DC. Microb. Pathog. 2018, 116, 44–48.
  80. Singh, P.; Nanda, A. Antimicrobial and antifungal potential of zinc oxide nanoparticles in comparison to conventional zinc oxide particles. J. Chem. Pharm. Res. 2013, 5, 457–463.
  81. Yu, J.; Zhang, W.; Li, Y.; Wang, G.; Yang, L.; Jin, J.; Chen, Q.; Huang, M. Synthesis, characterization, antimicrobial activity and mechanism of a novel hydroxyapatite whisker/nano zinc oxide biomaterial. Biomed. Mater. 2014, 10, 015001.
  82. Sirelkhatim, A.; Mahmud, S.; Seeni, A.; Kaus, N.H.M.; Ann, L.C.; Bakhori, S.K.M.; Hasan, H.; Mohamad, D. Review on zinc oxide nanoparticles: Antibacterial activity and toxicity mechanism. Nanomicro. Lett. 2015, 7, 219–242.
  83. Sukri, S.; Shameli, K.; Wong, M.; Teow, S.; Ismail, N. Cytotoxicity and antibacterial activities of plant-mediated synthesized zinc oxide (ZnO) nanoparticles using Punica granatum (pomegranate) fruit peels extract. J. Mol. Struct. 2019, 1189, 57–65.
  84. Happy, A.; Soumya, M.; Venkat Kumar, S.; Rajeshkumar, S.; Sheba, R.D.; Lakshmi, T.; Deepak Nallaswamy, V. Phyto-assisted synthesis of zinc oxide nanoparticles using Cassia alata and its antibacterial activity against Escherichia coli. Biochem. Biophys. Rep. 2019, 17, 208–211.
  85. Hantke, K. Bacterial zinc uptake and regulators. Curr. Opin. Microbiol. 2005, 8, 196–202.
  86. Singh, R.; Sripada, L.; Singh, R. Side effects of antibiotics during bacterial infection: Mitochondria, the main target in host cell. Mitochondrion 2014, 16, 50–54.
  87. Sensi, S.L.; Ton-That, D.; Sullivan, P.G.; Jonas, E.A.; Gee, K.R.; Kaczmarek, L.K.; Weiss, J.H. Modulation of mitochondrial function by endogenous Zn2+ pools. Proc. Natl. Acad. Sci. USA 2003, 100, 6157–6162.
  88. Sensi, S.L.; Yin, H.Z.; Carriedo, S.G.; Rao, S.S.; Weiss, J.H. Preferential Zn2+ influx through Ca2+-permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. Proc. Natl. Acad. Sci. USA 1999, 96, 2414–2419.
  89. Frederickson, C.J. Neurobiology of Zinc and Zinc-Containing Neurons. Int. Rev. Neurobiol. 1989, 31, 145–238.
  90. Bettger, W.J.; O’Dell, B.L. A critical physiological role of zinc in the structure and function of biomembranes. Life Sci. 1981, 28, 1425–1438.
  91. Vallee, B.L.; Falchuk, K.H. The biochemical basis of zinc physiology. Physiol. Rev. 1993, 73, 79–118.
  92. Brand, I.A.; Kleineke, J. Intracellular Zinc Movement and Its Effect on the Carbohydrate Metabolism of Isolated Rat Hepatocytes. J. Biol. Chem. 1996, 271, 1941–1949.
  93. Simons, T.J.B. Intracellular free zinc and zinc buffering in human red blood cells. J. Membr. Biol. 1991, 123, 63–71.
  94. Simons, T.J. Measurement of free Zn2+ ion concentration with the fluorescent probe mag-fura-2 (furaptra). J. Biochem. Biophys. Methods 1993, 27, 25–37.
  95. Zalewski, P.D.; Forbes, I.J.; Betts, W.H. Correlation of apoptosis with change in intracellular labile Zn(II) using zinquin [(2-methyl-8-p-toluenesulphonamido-6-quinolyloxy)acetic acid], a new specific fluorescent probe for Zn(II). Biochem. J. 1993, 296, 403–408.
  96. Williams, R.J.P.A. Introduction to the Biochemistry of Zinc; Springer International Publishing: Berlin, Germany, 1989; pp. 15–31.
  97. Palmiter, R.D.; Cole, T.B.; Findley, S.D. ZnT-2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration. EMBO J. 1996, 15, 1784–1791.
  98. Choi, D.; Yokoyama, M.; Koh, J. Zinc neurotoxicity in cortical cell culture. Neuroscience 1988, 24, 67–79.
  99. Provinciali, M.; Di Stefano, G.; Fabris, N. Dose-dependent opposite effect of zinc on apoptosis in mouse thymocytes. Int. J. Immunopharmacol. 1995, 17, 735–744.
  100. Telford, W.G.; Fraker, P.J. Preferential induction of apoptosis in mouse CD4+CD8+ alpha beta TCRloCD3 epsilon lo thymocytes by zinc. J. Cell Physiol. 1995, 164, 259–270.
  101. Yokoyama, M.; Koh, J.; Choi, D. Brief exposure to zinc is toxic to cortical neurons. Neurosci. Lett. 1986, 71, 351–355.
  102. Palmiter, R. Constitutive Expression of Metallothionein-III (MT-III), but Not MT-I, Inhibits Growth When Cells Become Zinc Deficient. Toxicol. Appl. Pharm. 1995, 135, 139–146.
  103. Palmiter, R.D. Protection against zinc toxicity by metallothionein and zinc transporter. Proc. Natl. Acad. Sci. USA 2004, 101, 4918–4923.
  104. Palmiter, R.D.; Cole, T.B.; Quaife, C.J.; Findley, S.D. ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc. Natl. Acad. Sci. USA 1996, 93, 14934–14939.
  105. Palmiter, R.; Findley, S. Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. Embo J. 1995, 14, 639–649.
  106. Cuajungco, M.P.; Lees, G.J. Zinc Metabolism in the Brain: Relevance to Human Neurodegenerative Disorders. Neurobiol. Dis. 1997, 4, 137–169.
  107. Maret, W. Zinc in Cellular Regulation: The Nature and Significance of “Zinc Signals”. Int. J. Mol. Sci 2017, 18, 2285.
  108. McMahon, R.J.; Cousins, R.J. Mammalian Zinc Transporters. J. Nutr. 1998, 128, 667–670.
  109. Howell, G.A.; Welch, M.G.; Frederickson, C.J. Stimulation-induced uptake and release of zinc in hippocampal slices. Nat. Cell Biol. 1984, 308, 736–738.
  110. Kambe, T.; Tsuji, T.; Hashimoto, A.; Itsumura, N. The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism. Physiol. Rev. 2015, 95, 749–784.
  111. Aniksztejn, L.; Charton, G.; Ben-Ari, Y. Selective release of endogenous zinc from the hippocampal mossy fibers in situ. Brain Res. 1987, 404, 58–64.
  112. Assaf, S.Y.; Chung, S.-H. Release of endogenous Zn2+ from brain tissue during activity. Nat. Cell Biol. 1984, 308, 734–736.
  113. Charton, G.; Rovira, C.; Ben-Ari, Y.; Leviel, V. Spontaneous and evoked release of endogenous Zn2+ in the hippocampal mossy fiber zone of the rat in situ. Exp. Brain Res. 1985, 58, 202–205.
  114. Bin, B.H.; Fukada, T.; Hosaka, T.; Yamasaki, S.; Ohashi, W.; Hojyo, S.; Miyai, T.; Nishida, K.; Yokoyama, S.; Hirano, T. Biochemical characterization of human ZIP13 protein: A homo-dimerized zinc transporter involved in the spondylocheiro dysplastic Ehlers-Danlos syndrome. J. Biol. Chem. 2011, 286, 40255–40265.
  115. Kukic, I.; Lee, J.K.; Coblentz, J.; Kelleher, S.L.; Kiselyov, K. Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter. Biochem. J. 2013, 451, 155–163.
  116. Raffaniello, R.D.; Wapnir, R.A. Zinc-induced metallothionein synthesis by Caco-2 cells. Biochem. Med. Metab. Biol. 1991, 45, 101–107.
  117. Thakran, P.; Leuschen, M.P.; Ebadi, M. Metallothionein induction in rat hippocampal neurons in primary culture. Vivo 1989, 3, 191–197.
  118. Valentine, R.A.; Jackson, K.A.; Christie, G.R.; Mathers, J.C.; Taylor, P.M.; Ford, D. ZnT5 variant B is a bidirectional zinc transporter and mediates zinc uptake in human intestinal Caco-2 cells. J. Biol. Chem. 2007, 282, 14389–14393.
  119. Cuajungco, M.P.; Lees, G.J. Nitric oxide generators produce accumulation of chelatable zinc in hippocampal neuronal perikarya. Brain Res. 1998, 799, 118–129.
  120. Jacob, C.; Maret, W.; Vallee, B.L. Control of zinc transfer between thionein, metallothionein, and zinc proteins. Proc. Natl. Acad. Sci. USA 1998, 95, 3489–3494.
  121. Jiang, L.-J.; Maret, W.; Vallee, B.L. The glutathione redox couple modulates zinc transfer from metallothionein to zinc-depleted sorbitol dehydrogenase. Proc. Natl. Acad. Sci. USA 1998, 95, 3483–3488.
  122. Wensink, J.; Molenaar, A.J.; Woroniecka, U.D.; Van den Hamer, C.J. Zinc uptake into synaptosomes. J. Neurochem. 1988, 50, 782–789.
  123. Colvin, R.A.; Holmes, W.R.; Fontaine, C.P.; Maret, W. Cytosolic zinc buffering and muffling: Their role in intracellular zinc homeostasis. Metallomics 2010, 2, 306–317.
  124. Cousins, R.J.; Liuzzi, J.P.; Lichten, L.A. Mammalian Zinc Transport, Trafficking, and Signals. J. Biol. Chem. 2006, 281, 24085–24089.
  125. Eide, D.J. Zinc transporters and the cellular Trafficking of zinc. Biochim. Et Biophys. Acta (Bba) Bioenerg. 2006, 1763, 711–722.
  126. Cuajungco, M.P.; Basilio, L.C.; Silva, J.; Hart, T.; Tringali, J.; Chen, C.C.; Biel, M.; Grimm, C. Cellular Zinc Levels Are Modulated by TRPML1-TMEM163 Interaction. Traffic 2014, 15, 1247–1265.
  127. Waberer, L.; Henrich, E.; Peetz, O.; Morgner, N.; Dotsch, V.; Bernhard, F.; Volknandt, W. The synaptic vesicle protein SV31 assembles into a dimer and transports Zn(2). J. Neurochem. 2017, 140, 280–293.
  128. Sanchez, V.B.; Ali, S.; Escobar, A.; Cuajungco, M.P. Transmembrane 163 (TMEM163) protein effluxes zinc. Arch. Biochem. Biophys. 2019, 677, 108166.
  129. Ohana, E.; Hoch, E.; Keasar, C.; Kambe, T.; Yifrach, O.; Hershfinkel, M.; Sekler, I. Identification of the Zn2+ binding site and mode of operation of a mammalian Zn2+ transporter. J. Biol. Chem. 2009, 284, 17677–17686.
  130. Maret, W. Metallothionein redox biology in the cytoprotective and cytotoxic functions of zinc. Exp. Gerontol. 2008, 43, 363–369.
  131. Krezoski, S.K.; Villalobos, J.; Shaw, C.F., 3rd; Petering, D.H. Kinetic lability of zinc bound to metallothionein in Ehrlich cells. Biochem. J. 1988, 255, 483–491.
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Math P. Cuajungco
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