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Chemical Compound Review

Copper Ion     copper(+2) cation

Synonyms: cupric ion, copper(2+), Copper ions, Cu+2, Cu++, ...
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Disease relevance of Copper ions

  • We have coupled hybrid quantum mechanics (density functional theory; Car-Parrinello)/molecular mechanics molecular dynamics simulations to a grand-canonical scheme, to calculate the in situ redox potential of the Cu(2+) + e(-) --> Cu(+) half reaction in azurin from Pseudomonas aeruginosa [1].
  • The Cu(II) sites of azurins, the blue single copper proteins, isolated from Pseudomonas aeruginosa and Alcaligenes spp [2].
  • The metallobiology of Cu(II) in Parkinson's disease is discussed by a comparative analysis with other Cu(II)-binding proteins involved in neurodegenerative disorders [3].
  • Consistent with the effects observed in vitro, coadministration of Cu(II) or Au(III) increased the in vivo potency of DPPE in mice bearing i.p. P388 leukemia [4].
  • The toxicity of soluble A beta was enhanced in the presence of Cu(II), which suggests the previously hypothesized role of A beta in generating oxidative stress [5].

Psychiatry related information on Copper ions


High impact information on Copper ions

  • Here we show that the amino-terminal domain of PrPC exhibits five to six sites that bind copper (Cu(II)) presented as a glycine chelate [10].
  • Using semiquantitative reverse transcription PCR, we show that Mramp mRNA levels in M. tuberculosis are upregulated in response to increases in ambient Fe(2+) and Cu(2+) between <1 and 5 microM concentrations and that this upregulation occurs in parallel with mRNA for y39, a putative metal-transporting P-type ATPase [11].
  • Research over the past few years, however, demonstrates that the prion protein is a copper binding protein with high selectivity for Cu(2+) [12].
  • The mechanism of oxidative deamination by CAOs is well understood, but there is a controversy surrounding the role of Cu(2+) in cofactor reoxidation [13].
  • We have investigated the organization, on the plasma membrane and in detergent-insoluble membrane vesicles, of two neuronal glycosylphosphatidylinositol-anchored (GPI) proteins: Thy-1, a negative regulator of transmembrane signalling; and prion protein, whose rapid endocytosis and Cu(2+) binding suggest that it functions in metal ion uptake [14].

Chemical compound and disease context of Copper ions

  • 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+) [15].
  • Bleomycin (Bm) in the culture broth of Streptomyces verticillus is complexed with Cu(2+) (Cu(II)) [16].
  • The role of the active site Cu(2+) of phenylethylamine oxidase from Arthrobacter globiformis (AGAO) has been studied by substitution with other divalent cations, where we were able to remove >99.5% of Cu(2+) from the active site [17].
  • Using Escherichia coli thioredoxin as a model protein, we show that potential binding sites can be identified using the Cu(2+) ion, and that pseudocontact shifts induced by a Ni(2+) ion bound to one of these sites can provide valuable long-range structure information about the protein [18].
  • Copper X-ray absorption spectroscopy (XAS) has been used to examine the structures of the Cu(II) and Cu(I) forms of the cytochrome bo3 quinol oxidase from Escherichia coli [19].

Biological context of Copper ions

  • The structural features of the Cu(2+) binding sites have now been characterized and are providing important clues about the normal function of the prion protein and perhaps how metals or loss of protein function play a role in disease [12].
  • The revertant phenotype is attributed to a decreased internal concentration of Cu(II) [20].
  • These experiments demonstrate that electron transport from the Fe(II)-heme to site-specifically bound Cu(II) can be mediated through multiple pathways in sperm whale Mb [21].
  • Copper ion homeostasis in yeast is maintained through regulated expression of genes involved in copper ion uptake, Cu(I) sequestration, and defense against reactive oxygen intermediates [22].
  • 1,2,4-Benzenetriol-induced DNA damage was inhibited by the addition of a Cu(I)-specific chelating agent, bathocuproine, and was accelerated by the addition of Cu(II) [23].

Anatomical context of Copper ions

  • Low density lipoproteins (LDL) isolated from WHHL rabbits under treatment with probucol (group B) were shown to be highly resistant to oxidative modification by cupric ion and to be minimally recognized by macrophages [24].
  • Damage was induced either in vivo by exposing cultured human male fibroblasts to H2O2 or in vitro by exposing purified genomic DNA to H2O2 plus ascorbate in the presence of Cu(II), Fe(III), or Cr(VI) metal ions [25].
  • EPR and magnetic susceptibility characterizations of the membranes indicate the presence of an exchange-coupled trinuclear Cu(II) cluster when the bulk of the copper ions is oxidized [26].
  • Kinetics of Cu(II) transport and accumulation by hepatocytes from copper-deficient mice and the brindled mouse model of Menkes disease [27].
  • Incubation of brain microsomes with Cu(II) generated approximately 30-kDa proteinase K-resistant PrP [7].

Associations of Copper ions with other chemical compounds

  • We have prepared synthetically a pentapeptide that contains this putative binding site and find that it not only has high affinity for binding Cu(II) and Zn(II) ions, but that it also undergoes a dramatic transition to an alpha-helical structure upon metal ion binding [28].
  • His-116 appears to play a minor role in the overall redox activity of Mb, but its involvement shows that Mb has the ability to reduce Cu(II) through a histidine residue located more than 20 A from the Fe(II)-heme [21].
  • Finally, the possible role of this trinuclear (type 2-type 3) Cu(II) active site in enabling the irreversible reduction of dioxygen to water is considered [29].
  • Oxidation of the zymogens Glu-plasminogen and single-chain urokinase-type plasminogen activator by Cu(II) and ascorbate resulted in the failure of these molecules to generate active enzymes when treated with plasminogen activators or plasmin, respectively [30].
  • Therefore, in an attempt to characterize unique and shared responses to chemically similar metals, we have reconstructed physiological behaviors of Halobacterium NRC-1, an archaeal halophile, in sublethal levels of Mn(II), Fe(II), Co(II), Ni(II), Cu(II), and Zn(II) [31].

Gene context of Copper ions

  • We have therefore used a range of complementary spectroscopies to characterize the coordination of Cu(2+) to Abeta in solution [6].
  • We show here that Cu(II) is equally efficient at repressing FRE1 transcription and is an excellent substrate for the Fre1p reductase [32].
  • Copper ion-sensing transcription factor Mac1p post-translationally controls the degradation of its target gene product Ctr1p [33].
  • The EPR spectrum of this Fet3p showed the presence of one type 1 Cu(II) and one type 2 Cu(II) (A parallel = 91 and 190 x 10(-4) cm-1, respectively) [34].
  • The high affinity uptake systems for iron and copper ions in Saccharomyces cerevisiae involve metal-specific permeases and two known cell surface Cu(II) and Fe(III) metalloreductases, Fre1 and Fre2 [35].

Analytical, diagnostic and therapeutic context of Copper ions

  • We determined the structure of the hydrated Cu(II) complex by both neutron diffraction and first-principles molecular dynamics [36].
  • Cupric ion, a thiol oxidant, caused naloxone-reversible analgesia when injected intracerebroventricularly in mice; its potency was close to that of morphine [37].
  • Using a quantitative ratiometric PCR technique, we demonstrate a fourfold decrease in Mramp/y39 mRNA ratios from organisms grown in 5-70 microM Cu(2+) [11].
  • The serum proteins/peptides were analyzed with 2 types of ProteinChip arrays, IMAC30 arrays loaded with copper (II) ion and CM10 (weak cation exchange) arrays [38].
  • Circular dichroism spectra indicate a distinctive structuring of the octarepeat region on Cu(II) binding [39].


  1. Role of protein frame and solvent for the redox properties of azurin from Pseudomonas aeruginosa. Cascella, M., Magistrato, A., Tavernelli, I., Carloni, P., Rothlisberger, U. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  2. Long-range intramolecular electron transfer in azurins. Farver, O., Pecht, I. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  3. Structural characterization of copper(II) binding to alpha-synuclein: Insights into the bioinorganic chemistry of Parkinson's disease. Rasia, R.M., Bertoncini, C.W., Marsh, D., Hoyer, W., Cherny, D., Zweckstetter, M., Griesinger, C., Jovin, T.M., Fernández, C.O. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  4. Modulation of the antitumor and biochemical properties of bis(diphenylphosphine)ethane with metals. Snyder, R.M., Mirabelli, C.K., Johnson, R.K., Sung, C.M., Faucette, L.F., McCabe, F.L., Zimmerman, J.P., Whitman, M., Hempel, J.C., Crooke, S.T. Cancer Res. (1986) [Pubmed]
  5. New insights on how metals disrupt amyloid beta-aggregation and their effects on amyloid-beta cytotoxicity. Yoshiike, Y., Tanemura, K., Murayama, O., Akagi, T., Murayama, M., Sato, S., Sun, X., Tanaka, N., Takashima, A. J. Biol. Chem. (2001) [Pubmed]
  6. Copper binding to the amyloid-beta (Abeta) peptide associated with Alzheimer's disease: folding, coordination geometry, pH dependence, stoichiometry, and affinity of Abeta-(1-28): insights from a range of complementary spectroscopic techniques. Syme, C.D., Nadal, R.C., Rigby, S.E., Viles, J.H. J. Biol. Chem. (2004) [Pubmed]
  7. Copper(II)-induced conformational changes and protease resistance in recombinant and cellular PrP. Effect of protein age and deamidation. Qin, K., Yang, D.S., Yang, Y., Chishti, M.A., Meng, L.J., Kretzschmar, H.A., Yip, C.M., Fraser, P.E., Westaway, D. J. Biol. Chem. (2000) [Pubmed]
  8. Mechanisms of Copper Ion Mediated Huntington's Disease Progression. Fox, J.H., Kama, J.A., Lieberman, G., Chopra, R., Dorsey, K., Chopra, V., Volitakis, I., Cherny, R.A., Bush, A.I., Hersch, S. PLoS ONE (2007) [Pubmed]
  9. Biosorption of copper(II) and zinc(II) from aqueous solution by Pseudomonas putida CZ1. Chen, X.C., Wang, Y.P., Lin, Q., Shi, J.Y., Wu, W.X., Chen, Y.X. Colloids and surfaces. B, Biointerfaces. (2005) [Pubmed]
  10. The cellular prion protein binds copper in vivo. Brown, D.R., Qin, K., Herms, J.W., Madlung, A., Manson, J., Strome, R., Fraser, P.E., Kruck, T., von Bohlen, A., Schulz-Schaeffer, W., Giese, A., Westaway, D., Kretzschmar, H. Nature (1997) [Pubmed]
  11. Mycobacterium tuberculosis expresses a novel pH-dependent divalent cation transporter belonging to the Nramp family. Agranoff, D., Monahan, I.M., Mangan, J.A., Butcher, P.D., Krishna, S. J. Exp. Med. (1999) [Pubmed]
  12. Copper binding in the prion protein. Millhauser, G.L. Acc. Chem. Res. (2004) [Pubmed]
  13. Tyrosine-derived quinone cofactors. Mure, M. Acc. Chem. Res. (2004) [Pubmed]
  14. Functionally different GPI proteins are organized in different domains on the neuronal surface. Madore, N., Smith, K.L., Graham, C.H., Jen, A., Brady, K., Hall, S., Morris, R. EMBO J. (1999) [Pubmed]
  15. The Inhibition of Mitochondrial Complex I (NADH:Ubiquinone Oxidoreductase) by Zn2+. Sharpley, M.S., Hirst, J. J. Biol. Chem. (2006) [Pubmed]
  16. The 1.6-A crystal structure of the copper(II)-bound bleomycin complexed with the bleomycin-binding protein from bleomycin-producing Streptomyces verticillus. Sugiyama, M., Kumagai, T., Hayashida, M., Maruyama, M., Matoba, Y. J. Biol. Chem. (2002) [Pubmed]
  17. Role of copper ion in bacterial copper amine oxidase: spectroscopic and crystallographic studies of metal-substituted enzymes. Kishishita, S., Okajima, T., Kim, M., Yamaguchi, H., Hirota, S., Suzuki, S., Kuroda, S., Tanizawa, K., Mure, M. J. Am. Chem. Soc. (2003) [Pubmed]
  18. Metal-protein interactions: structure information from Ni(2+)-induced pseudocontact shifts in a native nonmetalloprotein. Jensen, M.R., Led, J.J. Biochemistry (2006) [Pubmed]
  19. Cu XAS shows a change in the ligation of CuB upon reduction of cytochrome bo3 from Escherichia coli. Osborne, J.P., Cosper, N.J., Stälhandske, C.M., Scott, R.A., Alben, J.O., Gennis, R.B. Biochemistry (1999) [Pubmed]
  20. Metal ion regulated gene expression: use of a plastocyanin-less mutant of Chlamydomonas reinhardtii to study the Cu(II)-dependent expression of cytochrome c-552. Merchant, S., Bogorad, L. EMBO J. (1987) [Pubmed]
  21. Site-directed mutagenesis of histidine residues involved in Cu(II) binding and reduction by sperm whale myoglobin. Van Dyke, B.R., Bakan, D.A., Glover, K.A., Hegenauer, J.C., Saltman, P., Springer, B.A., Sligar, S.G. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  22. Copper-regulatory domain involved in gene expression. Winge, D.R. Prog. Nucleic Acid Res. Mol. Biol. (1998) [Pubmed]
  23. Human DNA damage induced by 1,2,4-benzenetriol, a benzene metabolite. Kawanishi, S., Inoue, S., Kawanishi, M. Cancer Res. (1989) [Pubmed]
  24. Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia. Kita, T., Nagano, Y., Yokode, M., Ishii, K., Kume, N., Ooshima, A., Yoshida, H., Kawai, C. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  25. Metal ion-dependent hydrogen peroxide-induced DNA damage is more sequence specific than metal specific. Rodriguez, H., Holmquist, G.P., D'Agostino, R., Keller, J., Akman, S.A. Cancer Res. (1997) [Pubmed]
  26. The nature of the copper ions in the membranes containing the particulate methane monooxygenase from Methylococcus capsulatus (Bath). Nguyen, H.H., Shiemke, A.K., Jacobs, S.J., Hales, B.J., Lidstrom, M.E., Chan, S.I. J. Biol. Chem. (1994) [Pubmed]
  27. Kinetics of Cu(II) transport and accumulation by hepatocytes from copper-deficient mice and the brindled mouse model of Menkes disease. Darwish, H.M., Hoke, J.E., Ettinger, M.J. J. Biol. Chem. (1983) [Pubmed]
  28. Is the olfactory receptor a metalloprotein? Wang, J., Luthey-Schulten, Z.A., Suslick, K.S. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  29. Low-temperature magnetic circular dichroism studies of native laccase: spectroscopic evidence for exogenous ligand bridging at a trinuclear copper active site. Allendorf, M.D., Spira, D.J., Solomon, E.I. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  30. Oxidative inactivation of plasmin and other serine proteases by copper and ascorbate. Lind, S.E., McDonagh, J.R., Smith, C.J. Blood (1993) [Pubmed]
  31. A systems view of haloarchaeal strategies to withstand stress from transition metals. Kaur, A., Pan, M., Meislin, M., Facciotti, M.T., El-Gewely, R., Baliga, N.S. Genome Res. (2006) [Pubmed]
  32. Evidence for Cu(II) reduction as a component of copper uptake by Saccharomyces cerevisiae. Hassett, R., Kosman, D.J. J. Biol. Chem. (1995) [Pubmed]
  33. Copper ion-sensing transcription factor Mac1p post-translationally controls the degradation of its target gene product Ctr1p. Yonkovich, J., McKenndry, R., Shi, X., Zhu, Z. J. Biol. Chem. (2002) [Pubmed]
  34. Spectral and kinetic properties of the Fet3 protein from Saccharomyces cerevisiae, a multinuclear copper ferroxidase enzyme. Hassett, R.F., Yuan, D.S., Kosman, D.J. J. Biol. Chem. (1998) [Pubmed]
  35. Metalloregulation of FRE1 and FRE2 homologs in Saccharomyces cerevisiae. Martins, L.J., Jensen, L.T., Simon, J.R., Keller, G.L., Winge, D.R., Simons, J.R. J. Biol. Chem. (1998) [Pubmed]
  36. First solvation shell of the Cu(II) aqua ion: evidence for fivefold coordination. Pasquarello, A., Petri, I., Salmon, P.S., Parisel, O., Car, R., Toth, E., Powell, D.H., Fischer, H.E., Helm, L., Merbach, A. Science (2001) [Pubmed]
  37. Opiate receptor function may be modulated through an oxidation-reduction mechanism. Marzullo, G., Hine, B. Science (1980) [Pubmed]
  38. Diagnosis of gastric cancer by serum proteomic fingerprinting. Poon, T.C., Sung, J.J., Chow, S.M., Ng, E.K., Yu, A.C., Chu, E.S., Hui, A.M., Leung, W.K. Gastroenterology (2006) [Pubmed]
  39. Copper binding to the prion protein: structural implications of four identical cooperative binding sites. Viles, J.H., Cohen, F.E., Prusiner, S.B., Goodin, D.B., Wright, P.E., Dyson, H.J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
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