Labile copper pool as the essential component of copper homeostasis system
Free copper ions do not exist in the cell, and cellular copper distribution relies on the bulk of copper complexes with different low-molecular ligands, which together constitute the kinetically labile cellular copper pool. The main copper ligands within this pool are probably reduced glutathione and metallothioneins, and some other compounds. The aim of this work is to characterise the main groups of labile copper-binding ligands in the cell, with special focus on the kinetical lability of copper ions in such complexes and their capability to generate reactive oxygen species. Reduced glutathione (GSH) is probably the main labile copper ligand in the cell, because it is found in millimolar concentrations inside the cell and has picomolar binding affinities for Cu(I) ions. Reduction of GSH content is accompanied by a significant decrease in copper uptake by the cell. The Cu(I)-GSH complex is probably involved in copper transfer from transport proteins, such as Ctr1, to copper chaperones, like Atx1. In several cases Cu-GSH was shown to be directly involved in copper donation in vivo to copper-containing proteins, such as Cu/Zn-SOD. Copper binding to GSH leads to its stabilization in Cu(I) oxidation state, which precludes copper participation in generation of hydroxyl radicals during Fenton-like reactions. Cu-GSH complex is probably able to generate superoxide anions, but this process occurs as a result of cysteine oxidation, with copper remaining in the Cu(I) state. Significant part of labile copper ligands may be implemented by metallothioneins -small cysteine-rich proteins, which bind ions of different d10-metals, including Cu(I), with the formation of polynuclear Cu-S clusters. Despite Cu(I) ions are bound to cysteine residues with high affinity, a significant part of them retains the kinetic lability and is able to transfer from metallothioneins to other ligands. Metallothioneins are capable to receive copper from Cu-GSH complex in vivo, and to deliver copper ions in vitro to different proteins, such as Cu,Zn-SOD, laccase and stellacyanin. Metallothioneins are likely to be involved in copper distribution in the cell and sequestration of excessive copper ions. Copper in Cu-MT is bound in Cu(I) oxidation state and is redox-inactive, thus it is incapable of generating highly active reactive oxygen species. There are some other possible constituents of the labile copper pool in the cell. A significant part of mitochondrial copper is bound with anionic copper ligand named CuL, which chemical nature is unknown. This ligand is probably involved in copper transport from cytosol to copper-containing proteins in mitochondria. Phytochelatins may play a role similar to that of metallothioneins in copper homeostasis. Phytochelatins are small peptides produced from glutathione, which bind copper ions within Cu-S clusters. Phytochelatins were able to donate bound copper ions to diamine oxidase in vitro. There can be also other ligands of labile copper in the cell, whose chemical nature is still to be identified.
Download file
Counter downloads: 349
Keywords
медь, лабильный пул, АФК, глутатион, copper, labile pool, reactive oxygen species, metallothioneins, glutathione, металлотионеиныAuthors
| Name | Organization | |
| Zlobin Ilya E. | Timiryazev Institute of Plant Physiology, Russian Academy of Sciences (Moscow) | ilya.zlobin.90@mail.ru |
References
Prutz W.A. Interaction between glutathione and Cu(II) in the vicinity of nucleic acids // Biochem. J. 1994. Vol. 302. P. 373 -382.
Tottey S., Waldron K.J., Firbank S.J., Reale B., Bessant C., Katsuko S., Cheek T.R., Gray J., BanfieldM.J., Dennison C., Robinson N.J. Protein-folding location can regulate manganese binding versus copper- or zinc-binding // Nature. 2008. Vol. 455. P. 1138-1142.
Xiao Z., Brose J., Schimo S., Ackland S.M., La Fontaine S., Wedd A.G. Unification of the copper(I) binding affinities of the metallochaperones Atx1, Atox1, and related proteins: Detection probes and affinity standards // J. Biol. Chem. 2011. Vol. 286, № 13. P. 1104711055.
Kohen R., Nyska A. Oxidation of biological systems: Oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification // Toxicol. Pathol. 2002. Vol. 30, № 6. P. 620-650.
Valko M., MorrisH., CroninM.T.D. Metals, toxicity and oxidative stress // Curr. Med. Chem. 2005. Vol. 12, № 10. P. 1161-1208.
Rae T.D., SchmidtP.J., PufahlR.A., Culotta V.C., O'Halloran T. V. Undetectable intracellular free copper: The requirement of a copper chaperone for superoxide dismutase // Science. 1999. Vol. 284, № 5415. P. 805-808.
Changela A., Chen K., Xue Y., Holschen J., Outten C.E., O'Halloran T.V., Mondragon A. Molecular basis of metal-ion selectivity and zeptomolar sensitivity by CueR // Science. 2003. Vol. 301, № 5638. P. 1383-1387.
Samuni A., Chevion M., Czapski G. Unusual copper-induced sensitization of the biological damage due to superoxide radicals // J. Biol. Chem. 1981. Vol. 256, № 24. P. 12632-12635.
Chevion M. A site-specific mechanism for free radical induced biological damage: The essential role of redox-active transition metals // Free Radical Bio. Med. 1988. Vol. 5, № 1. P. 27-37.
Yamamoto K., Kawanishi S. Hydroxyl free radical is not the main active species in site-specific DNA damage induced by copper(II) ion and hydrogen peroxide // J. Biol. Chem. 1989. Vol. 264, № 26. P. 15435-15440.
Sayre L.W., Perry G., Harris P.L.R., Liu Y., Schubert K.A., Smith M.A. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals // J. Neurochem. 2001. Vol. 74, № 1. P. 270-297.
Rubino J.T., Franz K.J. Coordination chemistry of copper proteins: How nature handles a toxic cargo for essential function // J. Inorg. Biochem. 2012. Vol. 107, № 1. P. 129-143.
Waldron K.J., Robinson N.J. How do bacterial cells ensure that metalloproteins get the correct metal? // Nat. Rev. Microbiol. 2009. Vol. 7. P. 25-35.
Maryon E.B., Molloy S.A., Kaplan J.H. Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1 // Am. J. Physiol. Cell Physiol. 2013. Vol. 304, № 8. P. 768-779.
Dodani S.C., Firl A., Chan J., Nam C.I., Aron A.T., Onak C.S., Ramos-Torres K.M., Paek J., Webster C.M., Feller M.B., Chang C.J. Copper is an endogenous modulator of neural circuit spontaneous activity // P. Natl. Acad. Sci. USA. 2014. Vol. 111, № 46. P. 16280-16285.
Miras R., Morin I., Jacquin O., Cuillel M., Guillain F., Mintz E. Interplay between glutathione, Atx1 and copper. 1. Copper(I) glutathionate induced dimerization of Atx1 // J. Biol. Inorg. Chem. 2008. Vol. 13, № 13. P. 195-205.
Poger D., Fillaux C., Miras R., Crouzy S., Delange P., Mintz E., Auwer C.D., Ferrand M. Interplay between glutathione, Atx1 and copper: X-ray absorption spectroscopy determination of Cu(I) environment in an Atx1 dimer // J. Biol. Inorg. Chem. 2008. Vol. 13, № 8. P. 1239-1248.
Banci L., Bertini I., Ciofi-Baffoni S., Kozyreva T., Zovo K., Palumaa P. Affinity gradients drive copper to cellular destinations // Nature. 2010. Vol. 465. P. 645-648.
Valko M., Rhodes C.J., Moncol J., Izakovic M., Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer // Chem.-Biol. Interact. 2006. Vol. 160, № 1. P. 1-40.
Freedman J.H., Ciriolo M.R., Peisach J. The role of glutathione in copper metabolism and toxicity // J. Biol. Chem. 1989. Vol. 264, № 10. P. 5598-5605.
Ferruzza S., Sambuy Y., Ciriolo M.R., De Martino A., Santaroni P., Potilio G., Scarino M.-L. Copper uptake and intracellular distribution in the human intestinal Caco-2 cell line // Biometals. 2000. Vol. 2000, № 13. P. 179-185.
Huffman D.L., O'Halloran T.V. Function, structure, and mechanism of intracellular copper trafficking proteins // Anu. Rev. Biochem. 2001. Vol. 70. P. 677-701.
Portnoy M., Schmidt P., Rogers R., Culotta V. Metal transporters that contribute copper to metallochaperones in Saccharomyces cerevisiae // Mol. Genet. Genomics. 2001. Vol. 265, № 5. P. 873-882.
Leitch J.M., Jensen L.T., Bouldin S.D., Outten C.E., Hart P.J., Culotta V.C. Activation of Cu,Zn-superoxide dismutase in the absence of oxygen and the copper chaperone CCS // J. Biol. Chem. 2009. Vol. 284. P. 21863-21871.
Carroll M.C., Girouard J.B., Ulloa J.L., Subramaniam J.R., WongP.C., Valentine J.S., Culotta V.C. Mechanisms for activating Cu- and Zn-containing superoxide dismutase in the absence of the CCS Cu chaperone // P. Natl. Acad. Sci. USA. 2004. Vol. 101, № 21. P. 5964-5969.
Jensen L.T., Culotta V.C. Activation of CuZn superoxide dismutases from Caenorhabditis elegans does not require the copper chaperone CCS // J. Biol. Chem. 2005. Vol. 280, № 50. P. 41373-41379.
CirioloM.R., DesideriA., PaciM., Rotilio G. Reconstitution of Cu,Zn-superoxide dismutase by the Cu(I)-glutathione complex // J. Biol. Chem. 1990. Vol. 265, № 19. P. 11030-11034.
Huang C.-S., Kuo W.-Y., Weiss C., Jinn T.-L. Copper chaperone-dependent and -independent activation of three copper-zinc superoxide dismutase homologs localized in different cellular compartments in Arabidopsis // Plant Physiol. 2012. Vol. 158. P. 737-746.
HannaP.M., Mason R.P. Direct evidence for inhibition of free radical formation from Cu(I) and hydrogen peroxide by glutathione and other potential ligands using the EPR spin-trapping technique // Arch. Biochem. Biophys. 1992. Vol. 295, № 1. P. 205-213.
Milne L., Nicotera P., Orrenius S., BurkittM.J. Effects of glutathione and chelating agents on copper-mediated DNA oxidation: Pro-oxidant and antioxidant properties of glutathione // Arch. Biochem. Biophys. 1993. Vol. 304, № 1. P. 102-109.
Spear N., Aust S.D. Hydroxylation of deoxyguanosine in DNA by copper and thiols // Arch. Biochem. Biophys. 1995. Vol. 317, № 1. P. 142-148.
Kachur A.V., Koch C.J., Blaglow J.E. Mechanism of copper-catalyzed oxidation of glutathione // Free Rad. Res. 1998. Vol. 28, № 3. P. 259-269.
Pecci L., Montefoschi G., Musci G., Cavallini D. Novel findings on the copper catalysed oxidation of cysteine // Amino Acids. 1997. Vol. 13, № 3-4. P. 355-367.
Rigo A., Corazza A., di Paolo M.L., Rossetto M., Ugolini R., Scarpa M. Interaction of copper with cysteine: Stability of cuprous complexes and catalytic role of cupric ions in anaerobic thiol oxidation // J. Inorg. Biochem. 2004. Vol. 98, № 9. P. 1495-1501.
Carrasco-Pozo C., Aliaga M.E., Olea-Azar C., Speisky H. Double edge redox-implications for the interaction between endogenous thiols and copper ions: In vitro studies // Bioorgan. Med. Chem. 2008. Vol. 16, № 22. P. 9795-9803.
Speisky H., Gomez M., Carrasco-Pozo C., Pastene E., Lopez-Alarcon C., Olea-Azar C. Cu(I)-glutathione complex: A potential source of superoxide radicals generation // Bioorgan. Med. Chem. 2008. Vol. 16, № 13. P. 6568-6574.
Speisky H., Gomez M., Burgos-Bravo F., Lopez-Alarcon C., Jullian C., Olea-Azar C., Aliaga M.E. Generation of superoxide radicals by copper-glutathione complexes: Redox-consequences associated with their interaction with reduced glutathione // Bioorgan. Med. Chem. 2009. Vol. 17, № 5. P. 1803-1810.
Pountney D.L., Schauwecker I., Zarn J., Vasak M. Formation of mammalian Cu8-metallothionein in vitro: Evidence for the existence of two Cu(I)4-thiolate clusters // Biochemistry. 1994. Vol. 33, № 32. P. 9699-9705.
Romero-IsartN., VasakM. Advances in the structure and chemistry of metallothioneins // J. Inorg. Biochem. 2002. Vol. 88, № 3-4. P. 388-396.
Deters D., Hartmann H.-J., Weser U. Transient thiyl radicals in yeast copper(I) thionein // BBA-Struct. M. 1994. Vol. 1208, № 2. P. 344-347.
HamerD.H. Metallothionein1,2 // Ann. Rev. Biochem. 1986. Vol. 55. P. 913-951.
BeltraminiM., MungerK., Germann U.A., Lerch K. Luminescence emission from the Cu(I)-thiolate complex in metallothioneins // Metallothionein II. Proceedings of the «Second International Meeting on Metallothionein and Other Low Molecular Weight Metal-binding Proteins» / Eds Kagi J.H.R., Kojima Y. Zurich, 1987. P. 237-241.
Byrd J., BergerR.M., McMillingD.R., Wright C.F., HamerD., Winge D.R. Characterization of the copper-thiolate cluster in yeast metallothionein and two truncated mutants // J. Biol. Chem. 1988. Vol. 263, № 14. P. 6688-6694.
Calderone V., Dolderer B., Hartmann H.-J., Echner H., Luchinat C., Del Blanco C., Mangani S., Weser U. The crystal structure of yeast copper thionein: The solution of a long-lasting enigma // PNAS. 2005. Vol. 102, № 1. P. 51-56.
Vaher M., Romero-Isart N., VasakM., Palumaa P. Reactivity of Cd7-metallothionein with Cu(II) ions: evidence for a cooperative formation of Cd3,Cu(I)5-metallothionein // J. Inorg. Biochem. 2001. Vol. 83, № 1. P. 1-6.
Liu SX., Fabisiak J.P., Tyurin V.A., Borisenko G.G., Pitt B.R., Lazo J.S., Kagan V.E. Reconstitution of apo-superoxide dismutase by nitric oxide-induced copper transfer from metallothioneins // Chem. Res. Toxicol. 2000. Vol. 13, № 9. P. 922-931.
Weser U., Hartmann H.-J. Differently bound copper(I) in yeast Cu8-thionein // BBA-Struct. M. 1988. Vol. 953. P. 1-5.
ChenP., OnanaP.,ShawC.F., Petering D.H. Characterization ofcalfliver Cu,Zn-metallothionein: Naturally variable Cu and Zn stoichiometries // Biochem. J. 1996. Vol. 317. P. 389-394.
Hartmann H.-J., Li Y.-J., Weser U. Analogous copper(I) coordination in metallothionein from yeast and the separate domains of the mammalian protein // Biometals. 1992. Vol. 5, № 3. P. 187-191.
Pickering I.J., George G.N., Dameron C.T., Kurz B., Winge D.R., Dance I.G. X-ray absorption spectroscopy of cuprous-thiolate clusters in proteins and model systems // J. Am. Chem. Soc. 1993. Vol. 115, № 21. P. 9498-9505.
Vasak M. Dynamic metal-thiolate cluster structure of metallothioneins // Environ. Health Perspect. 1986. Vol. 65. P. 193-197.
Stephenson G.F., Chan H.M., Cherian M.G. Copper-metallothionein from the toxic milk mutant mouse enhances lipid peroxidation initiated by an organic hydroperoxide // Toxicol. Appl. Pharm. 1994. Vol. 125, № 1. P. 90-96.
Oikawa S., Kurasaki M., Kojima Y., Kawanishi S. Oxidative and nonoxidative mechanisms of site-specific DNA cleavage induced by copper-containing metallothioneins // Biochemistry. 1995. Vol. 34, № 27. P. 8763-8770.
Fabisiak J.P., Pearce L.L., Borisenko G.G., Tyurina Y.Y., Tyurin V.A., Razzack J., Lazo J.S., Pitt B.R., Kagan V.E. Bifunctional anti-/prooxidant potential of metallothionein: redox signaling of copper binding and release // Antioxid. Redox Sign. 2008. Vol. 1, № 3. P. 349364.
Suzuki K.T., Maitani T. Metal-dependent properties of metallothionein. Replacement in vitro of zinc in zinc-thionein with copper // Biochem. J. 1981. Vol. 199. P. 289-295.
Carpene E., Andreani G., Isani G. Metallothionein functions and structural characteristics // J. Trace Elem. Med. Bio. 2007. Vol. 21, S1. P. 35-39.
Hartmann H.-J., Morpurgo L., Desideri A., Rotilio G., Weser U. Reconstitution of stellacyanin as a case of direct Cu(I) transfer between yeast copper thionein and 'blue' copper apoprotein // FEBS lett. 1983. Vol. 152, № 1. P. 94-96.
Freedman J.H., Peisach J. Intracellular copper transport in cultured hepatoma cells // Biochem. Bioph. Res. Co. 1989. Vol. 164, № 1. P. 134-140.
Morpurgo L., Hartmann H.J., Desideri A., Weser U., Rotilio G. Yeast copper-thionein can reconstitute the Japanese-lacquer-tree (Rhus vernicifera) laccase from the Type 2-copper-depleted enzyme via a direct copper(I)-transfer mechanism // Biochem. J. 1983. Vol. 211. P. 515-517.
Cobine P.A., Ojeda L.D., Rigby K.M., Winge D.R. Yeast contain a non-proteinaceous pool of copper in the mitochondrial matrix // J. Biol. Chem. 2004. Vol. 279, №14. P. 14447-14455.
Cobine P.A., Pierrel F., Bestwick M.L., Winge D.R. Mitochondrial matrix copper complex used in metallation of cytochrome oxidase and superoxide dismutase // J. Biol. Chem. 2006. Vol. 281, № 48. P. 36552-36559.
Mehra R.K., Winge D.R. Cu(I) binding to the Schizosaccharomyces pombe y-glutamyl peptides varying in chain lengths // Arch. Biochem. Biophys. 1988. Vol. 265, № 2. P. 381389.
Reese R.N., Mehra R.K., Tarbet E.B., Winge D.R. Studies on the y-glutamyl Cu-binding peptide from Schizosaccharomyces pombe // J. Biol. Chem. 1988. Vol. 263, № 9. P. 41864192.
Winge D.R. Copper coordination in metallothionein // Method. Enzymol. 1991. Vol. 205. P. 458-469.
Thumann J., Grill E., Winnacker E.-L., Zenk M.H. Reactivation of metal-requiring apoenzymes by phytochelatin-metal complexes // FEBS Lett. 1991. Vol. 284, № 1. P. 66-69.
Yang L., McRae R., Henary M.M., Patel R., Lai B., Vogt S., Fahrni C. Imaging of the intracellular topography of copper with a fluorescent sensor and by synchrotron x-ray fluorescence microscopy // PNAS USA. 2005. Vol. 102, № 32. P. 11179-11184.
Bi W.X., Kong F., Hu X.Y., Cui X. Role of glutathione in detoxification of copper and cadmium by yeast cells having different abilities to express Cup1 protein // Toxicol. Mech. Method. 2007. Vol. 17, № 6. P. 371-378.
Labile copper pool as the essential component of copper homeostasis system | Vestnik Tomskogo gosudarstvennogo universiteta. Biologiya - Tomsk State University Journal of Biology. 2015. № 3 (31) .
Download full-text version
Counter downloads: 2106