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Chemical Compound Review

Zinc dication     zinc(+2) cation

Synonyms: Zinc 2+, Zinc cation, AGN-PC-00S500, zinc ion, Zn+2, ...
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Disease relevance of ZINC

  • We report here that a protein of relative molecular mass 19,000 (Mr = 19 K) encompassing the DNA-binding domain of the glucocorticoid receptor that has been overexpressed in Escherichia coli and purified to homogeneity reversibly ligates two Zn(II) or Cd(II) ions [1].
  • The crystal structure of MutM from an extreme thermophile, Thermus thermophilus HB8, was determined at 1.9 A resolution with multiwavelength anomalous diffraction phasing using the intrinsic Zn(2+) ion of the zinc finger [2].
  • Zn(2+): a novel ionic mediator of neural injury in brain disease [3].
  • Modulation of the N-methyl-d-aspartate (NMDA)-selective glutamate receptors by extracellular protons and Zn(2+) may play important roles during ischemia in the brain and during seizures [4].
  • Zinc (II) and the single-stranded DNA binding protein of bacteriophage T4 [5].

Psychiatry related information on ZINC

  • More speculatively, Zn(2+) dis-homeostasis might also contribute to some degenerative conditions, including Alzheimer's disease [3].
  • Neonatal chickens were injected intraventricularly with Ni(II), Pd(II), Cu(II) or Zn(II) complex of TRH and the potencies of stimulating locomotor activity were compared with that of TRH, Ni(II)-TRH was more potent than the ligand while Pd(II)-TRH was inert [6].

High impact information on ZINC


Chemical compound and disease context of ZINC

  • Here, we describe the effects of Zn(2+) on complex I to define whether complex I may contribute to mediating the pathological effects of zinc in states such as ischemia and to determine how Zn(2+) can be used to probe the mechanism of complex I. Zn(2+) inhibits complex I more strongly than Mg(2+), Ca(2+), Ba(2+), and Mn(2+) to Cu(2+) or Cd(2+) [11].
  • Human membrane type 4 MMP CD (MT4-MMPCD) protein, expressed as inclusion bodies in Escherichia coli, was purified to homogeneity and refolded in the presence of Zn(2+) and Ca(2+) [12].
  • Metallo-beta-lactamase L1 from Stenotrophomonas maltophilia is a dinuclear Zn(II) enzyme that contains a metal-binding aspartic acid in a position to potentially play an important role in catalysis [13].
  • Reconstitution of metal-free recombinant Escherichia coli type I IDI with several divalent metals-Mg(2+), Mn(2+), Zn(2+), Co(2+), Ni(2+), and Cd(2+)-generated active enzyme [14].
  • Preincubation of cortical cultures with IGF-I increased arachidonic acid (AA)-induced cytotoxicity, and AA increased Zn(2+) toxicity, which suggested the involvement of COX activity in these cellular responses [15].

Biological context of ZINC

  • The results presented here define the beta-Lact/beta-CASP domain of Artemis as the minimal core catalytic domain needed for V(D)J recombination and suggest that Artemis uses one or two Zn(II) ions to exert its catalytic activity, like bacterial class B beta-Lact enzymes hydrolyzing beta-lactam compounds [16].
  • Thus, the hyperekplexia phenotype of Glra1(D80A) mice is due to the loss of Zn(2+) potentiation of alpha1 subunit containing GlyRs, indicating that synaptic Zn(2+) is essential for proper in vivo functioning of glycinergic neurotransmission [17].
  • Cellular functions require adequate homeostasis of several divalent metal cations, including Mg(2+) and Zn(2+) [18].
  • Biochemical analysis in mammalian cells indicates that high Zn(2+) concentration causes a dramatic increase of KSR phosphorylation [19].
  • Although the physiological significance of synaptic Zn(2+) release is little understood, it probably plays a modulatory role in synaptic transmission [3].

Anatomical context of ZINC

  • Fluorescent Zn(2+) indicators that do not penetrate membranes offer the prospect of rendering the release of Zn(2+) visible [20].
  • It is well established that some excitatory nerve terminals have high concentrations of Zn(2+) in their synaptic vesicles [20].
  • Moreover, I will argue that recent experiments suggest that, rather than being released, Zn(2+) is presented to the extracellular space firmly coordinated to presynaptic macromolecules [20].
  • Zinc ions are concentrated in the central nervous system and regulate GABA(A) receptors, which are pivotal mediators of inhibitory synaptic neurotransmission [21].
  • Conclusions: The effects of low-dose TPEN suggests that acidity within the TV/L compartment of the gastric gland may be regulated, at least in part, by its content of divalent cations such as Zn(2+), for which TPEN has high affinity [22].

Associations of ZINC with other chemical compounds

  • These reactions can take several forms, such as redox events (chemical reduction or oxidation), chelation of transition metals (chiefly Zn(2+), Mn(2+) and Cu(2+)) or S-nitrosylation [the catalyzed transfer of a nitric oxide (NO) group to a thiol group] [23].
  • In several cases, these disparate reactions can compete with one another for the same thiol group on a single cysteine residue, forming a molecular switch composed of a latticework of possible redox, NO or Zn(2+) modifications to control protein function [23].
  • Hyperekplexia Phenotype of Glycine Receptor alpha1 Subunit Mutant Mice Identifies Zn(2+) as an Essential Endogenous Modulator of Glycinergic Neurotransmission [17].
  • Small cysteine-rich proteins (metallothioneins) and related domains of some large proteins (e.g., lysine methyltransferases) bind tri- and tetranuclear zinc clusters with topologies resembling fragments of Zn(II) sulfide minerals [24].
  • One enzyme moiety is an adenylate cyclase and the other is a Zn(2+) metalloprotease, which is able to cleave MAPKKs [25].

Gene context of ZINC

  • We identified sur-7 by isolating a mutation that suppresses an activated ras allele, and showed that SUR-7 is a divergent member of the cation diffusion facilitator family of heavy metal ion transporters that is probably localized to the endoplosmic recticulum membrane and regulates cellular Zn(2+) concentrations [19].
  • The high resolution crystal structure of LTA4H in complex with the competitive inhibitor bestatin reveals a protein folded into three domains that together create a deep cleft harboring the catalytic Zn(2+) site [26].
  • They mainly consist of the amyloid peptide Abeta and display an abnormal content in Zn(2+) ions, together with many truncated, isomerized, and racemized forms of Abeta [27].
  • The Zn(2+)- and Ca(2+)-binding S100B protein is implicated in multiple intracellular and extracellular regulatory events [28].
  • In addition to Ca(2+), several members of the S100 protein family, including S100A2, bind Zn(2+) [29].

Analytical, diagnostic and therapeutic context of ZINC

  • Successful assembly of the METP peptide with Co(II), Zn(II), Fe(II/III), in the expected 2:1 stoichiometry, was proven by UV-visible and circular dichroism spectroscopies [30].
  • Using whole-cell recordings from amygdala slices, we demonstrated that activity-dependent release of chelatable Zn(2+) is required for the induction of spike timing-dependent long-term potentiation in cortical input to the amygdala implicated in fear learning [31].
  • Structural and kinetic analyses show that the complex of IIIGlc with glycerol kinase creates an intermolecular Zn(II) binding site with ligation identical to that of the zinc peptidase thermolysin [32].
  • The interactions of Zn(2+) with the open state indicate that the five pore-lining segments should rigidly tilt to enable the movement of their intracellular ends away from the axis of ion conduction, so as to open the constriction (i.e., the gate) [33].
  • Titration of apo-MTF-zf46 with Zn(II) reveals that the F4 domain binds Zn(II) significantly more tightly than do the other two finger domains [34].


  1. The function and structure of the metal coordination sites within the glucocorticoid receptor DNA binding domain. Freedman, L.P., Luisi, B.F., Korszun, Z.R., Basavappa, R., Sigler, P.B., Yamamoto, K.R. Nature (1988) [Pubmed]
  2. Crystal structure of a repair enzyme of oxidatively damaged DNA, MutM (Fpg), from an extreme thermophile, Thermus thermophilus HB8. Sugahara, M., Mikawa, T., Kumasaka, T., Yamamoto, M., Kato, R., Fukuyama, K., Inoue, Y., Kuramitsu, S. EMBO J. (2000) [Pubmed]
  3. Zn(2+): a novel ionic mediator of neural injury in brain disease. Weiss, J.H., Sensi, S.L., Koh, J.Y. Trends Pharmacol. Sci. (2000) [Pubmed]
  4. Molecular determinants of coordinated proton and zinc inhibition of N-methyl-D-aspartate NR1/NR2A receptors. Low, C.M., Zheng, F., Lyuboslavsky, P., Traynelis, S.F. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  5. Zinc (II) and the single-stranded DNA binding protein of bacteriophage T4. Gauss, P., Krassa, K.B., McPheeters, D.S., Nelson, M.A., Gold, L. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  6. The effect of metal complex of thyrotropin-releasing hormone on locomotor activity of neonatal chicken. Tonoue, T., Minagawa, S., Kato, N., Kan, M., Terao, T., Nonoyama, K., Ohki, K. Pharmacol. Biochem. Behav. (1979) [Pubmed]
  7. Mutations at a Zn(II) finger motif in the yeast eIF-2 beta gene alter ribosomal start-site selection during the scanning process. Donahue, T.F., Cigan, A.M., Pabich, E.K., Valavicius, B.C. Cell (1988) [Pubmed]
  8. The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair. Hopfner, K.P., Craig, L., Moncalian, G., Zinkel, R.A., Usui, T., Owen, B.A., Karcher, A., Henderson, B., Bodmer, J.L., McMurray, C.T., Carney, J.P., Petrini, J.H., Tainer, J.A. Nature (2002) [Pubmed]
  9. Dimerization of human growth hormone by zinc. Cunningham, B.C., Mulkerrin, M.G., Wells, J.A. Science (1991) [Pubmed]
  10. Metalloantibodies. Iverson, B.L., Iverson, S.A., Roberts, V.A., Getzoff, E.D., Tainer, J.A., Benkovic, S.J., Lerner, R.A. Science (1990) [Pubmed]
  11. The Inhibition of Mitochondrial Complex I (NADH:Ubiquinone Oxidoreductase) by Zn2+. Sharpley, M.S., Hirst, J. J. Biol. Chem. (2006) [Pubmed]
  12. Catalytic activities and substrate specificity of the human membrane type 4 matrix metalloproteinase catalytic domain. Wang, Y., Johnson, A.R., Ye, Q.Z., Dyer, R.D. J. Biol. Chem. (1999) [Pubmed]
  13. Metal binding Asp-120 in metallo-beta-lactamase L1 from Stenotrophomonas maltophilia plays a crucial role in catalysis. Garrity, J.D., Carenbauer, A.L., Herron, L.R., Crowder, M.W. J. Biol. Chem. (2004) [Pubmed]
  14. Escherichia coli type I isopentenyl diphosphate isomerase: structural and catalytic roles for divalent metals. Lee, S., Poulter, C.D. J. Am. Chem. Soc. (2006) [Pubmed]
  15. COX-2 Regulates the insulin-like growth factor I-induced potentiation of Zn(2+)-toxicity in primary cortical culture. Im, J.Y., Kim, D., Lee, K.W., Kim, J.B., Lee, J.K., Kim, D.S., Lee, Y.I., Ha, K.S., Joe, C.O., Han, P.L. Mol. Pharmacol. (2004) [Pubmed]
  16. The metallo-beta-lactamase/beta-CASP domain of Artemis constitutes the catalytic core for V(D)J recombination. Poinsignon, C., Moshous, D., Callebaut, I., de Chasseval, R., Villey, I., de Villartay, J.P. J. Exp. Med. (2004) [Pubmed]
  17. Hyperekplexia Phenotype of Glycine Receptor alpha1 Subunit Mutant Mice Identifies Zn(2+) as an Essential Endogenous Modulator of Glycinergic Neurotransmission. Hirzel, K., M??ller, U., Latal, A.T., H??lsmann, S., Grudzinska, J., Seeliger, M.W., Betz, H., Laube, B. Neuron (2006) [Pubmed]
  18. Cloning and characterization of a novel Mg(2+)/H(+) exchanger. Shaul, O., Hilgemann, D.W., de-Almeida-Engler, J., Van Montagu, M., Inz, D., Galili, G. EMBO J. (1999) [Pubmed]
  19. Modulation of KSR activity in Caenorhabditis elegans by Zn ions, PAR-1 kinase and PP2A phosphatase. Yoder, J.H., Chong, H., Guan, K.L., Han, M. EMBO J. (2004) [Pubmed]
  20. Imaging synaptic zinc: promises and perils. Kay, A.R. Trends Neurosci. (2006) [Pubmed]
  21. Zinc-mediated inhibition of GABA(A) receptors: discrete binding sites underlie subtype specificity. Hosie, A.M., Dunne, E.L., Harvey, R.J., Smart, T.G. Nat. Neurosci. (2003) [Pubmed]
  22. Divalent cations regulate acidity within the lumen and tubulovesicle compartment of gastric parietal cells. Gerbino, A., Hofer, A.M., McKay, B., Lau, B.W., Soybel, D.I. Gastroenterology (2004) [Pubmed]
  23. Cysteine regulation of protein function--as exemplified by NMDA-receptor modulation. Lipton, S.A., Choi, Y.B., Takahashi, H., Zhang, D., Li, W., Godzik, A., Bankston, L.A. Trends Neurosci. (2002) [Pubmed]
  24. How to hide zinc in a small protein. Blindauer, C.A., Sadler, P.J. Acc. Chem. Res. (2005) [Pubmed]
  25. Anthrax. Mock, M., Fouet, A. Annu. Rev. Microbiol. (2001) [Pubmed]
  26. Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation. Thunnissen, M.M., Nordlund, P., Haeggström, J.Z. Nat. Struct. Biol. (2001) [Pubmed]
  27. Structural changes of region 1-16 of the Alzheimer disease amyloid beta-peptide upon zinc binding and in vitro aging. Zirah, S., Kozin, S.A., Mazur, A.K., Blond, A., Cheminant, M., Ségalas-Milazzo, I., Debey, P., Rebuffat, S. J. Biol. Chem. (2006) [Pubmed]
  28. The zinc- and calcium-binding S100B interacts and co-localizes with IQGAP1 during dynamic rearrangement of cell membranes. Mbele, G.O., Deloulme, J.C., Gentil, B.J., Delphin, C., Ferro, M., Garin, J., Takahashi, M., Baudier, J. J. Biol. Chem. (2002) [Pubmed]
  29. Mapping the zinc ligands of S100A2 by site-directed mutagenesis. Stradal, T.B., Troxler, H., Heizmann, C.W., Gimona, M. J. Biol. Chem. (2000) [Pubmed]
  30. Miniaturized metalloproteins: application to iron-sulfur proteins. Lombardi, A., Marasco, D., Maglio, O., Di Costanzo, L., Nastri, F., Pavone, V. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  31. Synaptically released zinc gates long-term potentiation in fear conditioning pathways. Kodirov, S.A., Takizawa, S., Joseph, J., Kandel, E.R., Shumyatsky, G.P., Bolshakov, V.Y. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  32. Cation-promoted association of a regulatory and target protein is controlled by protein phosphorylation. Feese, M., Pettigrew, D.W., Meadow, N.D., Roseman, S., Remington, S.J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  33. Pore conformations and gating mechanism of a Cys-loop receptor. Paas, Y., Gibor, G., Grailhe, R., Savatier-Duclert, N., Dufresne, V., Sunesen, M., de Carvalho, L.P., Changeux, J.P., Attali, B. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  34. Conformational heterogeneity in the C-terminal zinc fingers of human MTF-1: an NMR and zinc-binding study. Giedroc, D.P., Chen, X., Pennella, M.A., LiWang, A.C. J. Biol. Chem. (2001) [Pubmed]
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