Advertisement

Molecular Medicine

, Volume 13, Issue 7–8, pp 371–375 | Cite as

Cellular Zinc and Redox Buffering Capacity of Metallothionein/Thionein in Health and Disease

  • Wolfgang Maret
  • Artur Krężel
Proceedings

Abstract

Zinc is involved in virtually all aspects of cellular and molecular biology as a catalytic, structural, and regulatory cofactor in over 1000 proteins. Zinc binding to proteins requires an adequate supply of zinc and intact molecular mechanisms for redistributing zinc ions to make them available at the right time and location. Several dozen gene products participate in this process, in which interactions between zinc and sulfur donors determine the mobility of zinc and establish coupling between cellular redox state and zinc availability. Specifically, the redox properties of metallothionein and its apoprotein thionein are critical for buffering zinc ions and for controlling fluctuations in the range of picomolar concentrations of “free” zinc ions in cellular signaling. Metallothionein and other proteins with sulfur coordination environments are sensitive to redox perturbations and can render cells susceptible to injury when oxidative stress compromises the cellular redox and zinc buffering capacity in chronic diseases. The implications of these fundamental principles for zinc metabolism in type 2 diabetes are briefly discussed.

Notes

Acknowledgment

This work was supported in part by a grant from the National Institutes of Health (GM 065388 to WM).

References

  1. 1.
    Hambidge M. (2000) Human zinc deficiency J. Nutr. 130:1344S–9S.CrossRefGoogle Scholar
  2. 2.
    Sandstead HH, Frederickson CJ, Penland JG. (2000) History of zinc related to brain function. J. Nutr. 130:496S–502S.CrossRefGoogle Scholar
  3. 3.
    Frederickson CJ, Koh J-Y, Bush AI. (2005) The neurobiology of zinc in health and disease. Nat. Rev. Neurosci. 6:449–62.CrossRefGoogle Scholar
  4. 4.
    Fong LYY, Jiang YB, Farber JL. (2006) Zinc deficiency potentiates induction and progression of lingual and esophageal tumors in p53-deficient mice. Carcinogenesis. 27:1489–96.CrossRefGoogle Scholar
  5. 5.
    Wang K et al. (2002) A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am. J. Hum. Genet. 71:66–73.CrossRefGoogle Scholar
  6. 6.
    Küry S et al. (2002) Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat. Genet. 31:239–40.CrossRefGoogle Scholar
  7. 7.
    Chowanadisai W, Lönnerdal B, Kelleher SL. (2006) Identification of a mutation in SLC30A2 (ZnT-2) in women with low milk zinc concentration that results in transient neonatal zinc deficiency. J. Biol. Chem. 281:39699–707.CrossRefGoogle Scholar
  8. 8.
    Cipriano C et al. (2006) Polymorphisms in MT1a gene coding region are associated with longevity in Italian Central female population. Biogerontology. 7:357–65.CrossRefGoogle Scholar
  9. 9.
    Sensi SL, Jeng JM. (2004) Rethinking the excitotoxic ionic milieu: the emerging role of Zn2+ in ischemic neuronal injury. Curr. Mol. Med. 4:87–111.CrossRefGoogle Scholar
  10. 10.
    Jacob C, Maret W, Vallee BL. (1998) Control of zinc transfer between thionein, metallothionein and zinc proteins. Proc. Natl. Acad. Sci. USA. 95:3489–94.CrossRefGoogle Scholar
  11. 11.
    Pattanaik A et al. (1994) Basal metallothionein in tumors: Widespread presence of apoprotein. J. Inorg. Biochem. 54:91–105.CrossRefGoogle Scholar
  12. 12.
    Yang Y, Maret W, Vallee BL. (2001) Differential fluorescence labeling of cysteinyl clusters uncovers high tissue levels of thionein. Proc. Natl. Acad. Sci. USA. 98:5556–9.CrossRefGoogle Scholar
  13. 13.
    Kreżel A, Maret W. (2007) Different redox states of metallothionein/thionein in biological tissue. Biochem. J. 402:551–8.CrossRefGoogle Scholar
  14. 14.
    Maret W et al. (1999) Inhibitory sites in enzymes: Zinc removal and reactivation by thionein. Proc. Natl. Acad. Sci. USA. 96:1936–40.CrossRefGoogle Scholar
  15. 15.
    Maret W, Vallee BL. (1998) Thiolate ligands in metallothionein confer redox activity on zinc clusters. Proc. Natl. Acad. Sci. USA. 95:3478–82.CrossRefGoogle Scholar
  16. 16.
    Maret W. (2006) Zinc coordination environments in proteins as redox sensors and signal transducers. Antioxid. Redox Signal. 8:1419–41.CrossRefGoogle Scholar
  17. 17.
    Haase H, Maret W. (2004) A differential assay for the reduced and oxidized states of metallothionein and thionein. Anal. Biochem. 333:19–26.CrossRefGoogle Scholar
  18. 18.
    Feng W et al. (2006) Metallothionein disulfides are present in metallothionein-overexpressing transgenic mouse heart and increase under conditions of oxidative stress. J. Biol. Chem. 281:681–7.CrossRefGoogle Scholar
  19. 19.
    Kreżel A, Maret W. (2006) Zinc buffering capacity of a eukaryotic cell at physiological pZn. J. Biol. Inorg. Chem. 11:1049–62.CrossRefGoogle Scholar
  20. 20.
    Kreżel A, Hao Q Maret W. (2007) The zinc/thiolate redox biochemistry of metallothionein and the control of zinc ion fluctuations in cell signaling. Arch. Biochem. Biophys. DOI:10.1016/j.abb.2007.02.017.Google Scholar
  21. 21.
    Maret W. (2004) Protein interface zinc sites: A role of zinc in the supramolecular assembly of proteins and in transient protein-protein interactions, in: Messerschmidt, A., Bode, W., and Cygler, M., eds., Handbook of Metalloproteins, Vol. 3, pp. 432–41, John Wiley, Chichester.Google Scholar
  22. 22.
    Kirlin WG et al. (1999) Glutathione redox potential in response to differentiation and enzyme inducers. Free Radic. Biol. Med. 27:1208–18.CrossRefGoogle Scholar
  23. 23.
    Woo ES, Monks A, Watkins SC, et al. (1997) Diversity of metallothionein content and sub-cellular localization in the National Cancer Institute tumor panel. Cancer Chemother. Pharmacol. 4:61–8.CrossRefGoogle Scholar
  24. 24.
    Haase H et al. (2006) Flow cytometric measurements of labile zinc in peripheral blood mononuclear cells. Anal. Biochem. 352:222–30.CrossRefGoogle Scholar
  25. 25.
    Maret W. (2005) Zinc and diabetes. BioMetals. 18:293–4.CrossRefGoogle Scholar
  26. 26.
    Sladek R et al. (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 445:881–5CrossRefGoogle Scholar
  27. 27.
    Chimienti F, Favier A, Seve M. (2005) ZnT-8, a pancreatic beta-cell-specific transporter. BioMetals. 18:313–7.CrossRefGoogle Scholar
  28. 28.
    Roussel A-M et al. (2003) Antioxidant effects of zinc supplementation in Tunisians with type 2 diabetes mellitus. J. Am. Coll. Nutr. 22:316–1.CrossRefGoogle Scholar
  29. 29.
    Schott-Ohly P et al. (2004) Prevention of spontaneous and experimentally induced diabetes in mice with zinc sulfate-enriched drinking water is associated with activation and reduction of NF-κB and AP-1 in islets, respectively. Exp. Biol. Med. 229:1177–85.CrossRefGoogle Scholar
  30. 30.
    Adachi Y et al. (2006) Oral administration of a zinc complex improves type 2 diabetes and metabolic syndromes. Biochem. Biophys. Res. Commun. 351:165–70.CrossRefGoogle Scholar
  31. 31.
    Ayaz M, Turan B. (2006) Selenium prevents diabetes-induced alterations in [Zn2+]i and metal-lothionein level of rat heart via restoration of cell redox cycle. Am. J. Physiol Heart Circ. Physiol. 290:1071–80.CrossRefGoogle Scholar
  32. 32.
    Chen Y, Maret W. (2001) Catalytic selenols couple the redox cycles of metallothionein and glutathione. Eur. J. Biochem. 268:3346–53.CrossRefGoogle Scholar
  33. 33.
    Wang J et al. (2006) Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation. Circulation. 113:544–54.CrossRefGoogle Scholar
  34. 34.
    Kang YJ. (1999) The antioxidant function of metallothionein in the heart. Proc. Soc. Exp. Biol. Med. 222:263–73.CrossRefGoogle Scholar
  35. 35.
    Barbato JC et al. (2007) Targeting of metallothionein by L-homocysteine. A novel mechanism for disruption of zinc and redox homeostasis. Arterioscler. Thromb. Vasc. Biol. 27:49–54.CrossRefGoogle Scholar
  36. 36.
    Scheede-Bergdahl C et al. (2005) Metallothionein-mediated antioxidant defense system and its response to exercise training are impaired in human type 2 diabetes. Diabetes. 54:3089–94.CrossRefGoogle Scholar
  37. 37.
    Beattie et al. (1998) Obesity and hyperleptinemia in metallothionein (-I and -II) null mice. Proc. Natl. Acad. Sci. USA. 95:358–63.CrossRefGoogle Scholar
  38. 38.
    Hao Q, Maret W. (2006) Aldehydes release zinc from proteins. A pathway from oxidative stress/lipid peroxidation to cellular functions of zinc. FEBS J. 273:4300–10.CrossRefGoogle Scholar
  39. 39.
    Haase H, Maret W. (2003) Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulin-like growth factor-1 signaling. Exp. Cell Res. 291:289–98.CrossRefGoogle Scholar
  40. 40.
    Haase H, Maret W. (2005) Fluctuations of cellular, available zinc modulate phosphorylation signaling. J. Trace Elem. Med. Biol. 19:37–42.CrossRefGoogle Scholar
  41. 41.
    Haase H, Maret W. (2005) Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants. BioMetals 18:333–8.CrossRefGoogle Scholar
  42. 42.
    St. Croix CM et al. (2005) Nitric oxide and zinc homeostasis in acute lung injury. Proc. Am. Thor. Soc. 2:236–42.CrossRefGoogle Scholar
  43. 43.
    Frederickson CJ, Maret W, Cuajungco MP. (2004) Zinc and excitotoxic brain injury: A new model. Neuroscientist. 10:18–25.CrossRefGoogle Scholar
  44. 44.
    Maret W, Sandstead HH. (2006) Zinc requirements and the risks and benefits of zinc supplementation. J. Trace Elem. Med. Biol. 20:3–18.CrossRefGoogle Scholar
  45. 45.
    Kang YJ, Zhou Z. (2005) Zinc prevention and treatment of alcoholic liver disease. Mol. Asp. Med. 26:391–404.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  1. 1.Division of Human Nutrition, Department of Preventive Medicine and Community HealthThe University of Texas Medical BranchGalvestonUSA
  2. 2.Department of AnesthesiologyThe University of Texas Medical BranchGalvestonUSA

Personalised recommendations