BioMetals

, Volume 22, Issue 1, pp 149–157 | Cite as

Molecular aspects of human cellular zinc homeostasis: redox control of zinc potentials and zinc signals

Article

Abstract

Zinc(II) ions are essential for all forms of life. In humans, they have catalytic and structural functions in an estimated 3,000 zinc proteins. In addition, they interact with proteins transiently when they regulate proteins or when proteins regulate cellular zinc re-distribution. As yet, these types of zinc proteins have been explored poorly. Therefore the number of zinc/protein interactions is potentially larger than that given by the above estimate. Confronted with such a wide range of functions, which affect virtually all aspects of cellular physiology, investigators have begun to elucidate the molecular mechanisms of cellular homeostatic control of zinc, especially the functions of transporter, sensor, and trafficking proteins, such as metallothioneins, in providing the correct amounts of zinc ions for the synthesis of zinc metalloproteins. The sulfur-containing amino acid cysteine in proteins has an important role in the cellular mobility of zinc ions. Sulfur-coordination environments provide sufficiently strong interactions with zinc ions; they can undergo fast ligand-exchange; and they can serve as molecular redox switches for zinc binding and release. For the cellular functions of zinc, the free zinc ion concentrations (zinc potentials, pZn = −log[Zn2+]) and the zinc buffering capacity are critically important parameters that need to be defined quantitatively. In the cytoplasm, free zinc ions are kept at picomolar concentrations as a minute fraction of the few hundred micromolar concentrations of total cellular zinc. However, zinc ion concentrations can fluctuate under various conditions. Zinc ions released intracellularly from the zinc/thiolate clusters of metallothioneins or secreted from specialized organelles are potent effectors of proteins and are considered zinc signals. The cellular zinc buffering capacity determines the threshold between physiological and pathophysiological actions of zinc ions. When drugs, toxins, other transition metal ions or reactive compounds compromise zinc buffering, large zinc ion fluctuations can injure cells through effects on redox biology and interactions of zinc ions with proteins that are normally not targeted.

Keywords

Zinc Redox biology Homeostatic control Metalloregulation Metallothionein 

Abbreviations

MT

Metallothionein

MTF-1

Metal response element (MRE)-binding transcription factor-1

Notes

Acknowledgments

This work was supported by Grant GM 065388 from the National Institutes of Health, the John Sealy Memorial Endowment Fund, a pilot project grant from the UTMB Claude Pepper Older Americans Independence Center, and a sponsored research agreement with Neurobiotex Inc, Galveston, TX.

References

  1. Adebodun F, Post JF (1995) Role of intracellar free Ca(II) and Zn(II) in dexamethasone-induced apoptosis and dexamethasone resistance in human leukemic CEM cell lines. J Cell Physiol 163:80–86. doi: 10.1002/jcp.1041630109 PubMedCrossRefGoogle Scholar
  2. Aizenman E, Stout AK, Hartnett KA et al (2000) Induction of neuronal apoptosis by thiol oxidation: putative role of intracellular zinc release. J Neurochem 75:1878–1888. doi: 10.1046/j.1471-4159.2000.0751878.x PubMedCrossRefGoogle Scholar
  3. Andreini C, Banci L, Bertini I et al (2006a) Zinc through the three domains of life. J Proteome Res 5:3173–3179. doi: 10.1021/pr0603699 PubMedCrossRefGoogle Scholar
  4. Andreini C, Banci L, Bertini I et al (2006b) Counting the zinc-proteins encoded in the human genome. J Proteome Res 5:196–201. doi: 10.1021/pr050361j PubMedCrossRefGoogle Scholar
  5. Arseniev A, Schultze P, Wörgötter E et al (1988) Three-dimensional structure of rabbit liver [Cd7]metallothionein-2a in aqueous solution determined by nuclear magnetic resonance. J Mol Biol 201:637–657. doi: 10.1016/0022-2836(88)90644-4 PubMedCrossRefGoogle Scholar
  6. Atar D, Backx PH, Appel MM et al (1995) Excitation-transcription coupling mediated by zinc influx through voltage-dependent calcium channels. J Biol Chem 270:2473–2477. doi: 10.1074/jbc.270.6.2473 PubMedCrossRefGoogle Scholar
  7. Auld DS (2001) Zinc coordination sphere in biochemical zinc sites. Biometals 14:271–313. doi: 10.1023/A:1012976615056 PubMedCrossRefGoogle Scholar
  8. Barbato JC, Catanescu O, Murray K 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. doi: 10.1161/01.ATV.0000251536.49581.8a PubMedCrossRefGoogle Scholar
  9. Benters J, Flögel U, Schäfer T et al (1997) Study of the interactions of cadmium and zinc ions with cellular calcium homeostasis using 19F-NMR spectroscopy. Biochem J 322:793–799PubMedGoogle Scholar
  10. Bernal PJ, Leelavanichkul K, Bauer E et al (2008) Nitric oxide-mediated zinc release contributes to hypoxic regulation of pulmonary vascular tone. Circ Res 102:1575–1583. doi: 10.1161/CIRCRESAHA.108.171264 PubMedCrossRefGoogle Scholar
  11. Bossy-Wetzel E, Talantova MV, Lee WD et al (2004) Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels. Neuron 41:351–365. doi: 10.1016/S0896-6273(04)00015-7 PubMedCrossRefGoogle Scholar
  12. Bozym RA, Thompson RB, Stoddard AK et al (2006) Measuring picomolar intracellular exchangeable zinc in PC-12 cells using a ratiometric fluorescence biosensor. ACS Chem Biol 1:103–111. doi: 10.1021/cb500043a PubMedCrossRefGoogle Scholar
  13. Brand IA, Kleineke JW (1996) Intracellular zinc movements and its effect on the carbohydrate metabolism of isolated rat hepatocytes. J Biol Chem 261:1941–1949Google Scholar
  14. Bray TM, Bettger WJ (1990) The physiological role of zinc as an antioxidant. Free Radic Biol Med 8:281–291. doi: 10.1016/0891-5849(90)90076-U PubMedCrossRefGoogle Scholar
  15. Chen Y, Maret W (2001) Catalytic selenols couple the redox cycles of metallothionein and glutathione. Eur J Biochem 268:3346–3353. doi: 10.1046/j.1432-1327.2001.02250.x PubMedCrossRefGoogle Scholar
  16. Choi DW, Koh JY (1998) Zinc and brain injury. Annu Rev Neurosci 21:347–375. doi: 10.1146/annurev.neuro.21.1.347 PubMedCrossRefGoogle Scholar
  17. Cima RR, Dubach JM, Wieland A et al (2006) Intracellular Ca2+ and Zn2+ signals during monochloramine-induced oxidative stress in isolated rat colon crypts. Am J Physiol Gastrointest Liver Physiol 290:250–261. doi: 10.1152/ajpgi.00501.2004 CrossRefGoogle Scholar
  18. Colgan SM, Austin RC (2007) Homocysteinylation of metallothionein impairs intracellular redox homeostasis. Arterioscler Thromb Vasc Biol 27:8–11. doi: 10.1161/01.ATV.0000254151.00086.26 PubMedCrossRefGoogle Scholar
  19. Colvin RA, Bush AI, Volitakis I et al (2008) Insights into Zn2+ homeostasis in neurons from experimental and modeling studies. Am J Physiol Cell Physiol 294:C726–C742. doi: 10.1152/ajpcell.00541.2007 PubMedCrossRefGoogle Scholar
  20. Cousins RJ, Liuzzi JP, Lichtlen LA (2006) Mammalian zinc transport, trafficking, and signals. J Biol Chem 281:24085–24089. doi: 10.1074/jbc.R600011200 PubMedCrossRefGoogle Scholar
  21. Eide DJ (2006) Zinc transporters and the cellular trafficking of zinc. Biochim Biophys Acta 1763:711–722. doi: 10.1016/j.bbamcr.2006.03.005 PubMedCrossRefGoogle Scholar
  22. Erfurt C, Roussa E, Thévenod F (2003) Apoptosis by Cd2+ or CdMT in proximal tubule cells: different uptake routes and permissive role of endo/lysosomal CdMT uptake. Am J Physiol Cell Physiol 285:C1367–C1376PubMedGoogle Scholar
  23. Feng W, Benz FW, Cai J et al (2006) Metallothionein disulfides are present in metallothionein-overexpressing transgenic mouse heart and increase under conditions of oxidative stress. J Biol Chem 281:681–687. doi: 10.1074/jbc.M506956200 PubMedCrossRefGoogle Scholar
  24. Frederickson CJ (2003) Imaging zinc: old and new tools. Sci STKE 2003(182):pe 18Google Scholar
  25. Frederickson CJ, Koh J-Y, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449–462. doi: 10.1038/nrn1671 PubMedCrossRefGoogle Scholar
  26. Gazaryan G, Krasnikov BF, Ashby GA et al (2002) Zinc is a potent inhibitor of thiol oxidoreductase activity and stimulates reactive oxygen species production by lipoamide dehydrogenase. J Biol Chem 277:10064–10072. doi: 10.1074/jbc.M108264200 PubMedCrossRefGoogle Scholar
  27. Grummt F, Weinmann-Dorsch C, Schneider-Schaulies J et al (1986) Zinc as a messenger of mitogenic inductions. Exp Cell Res 163:191–200. doi: 10.1016/0014-4827(86)90572-0 PubMedCrossRefGoogle Scholar
  28. Haase H, Maret W (2003) Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulin-like growth factor-1 signaling. Exp Cell Res 291:289–298. doi: 10.1016/S0014-4827(03)00406-3 PubMedCrossRefGoogle Scholar
  29. Haase H, Maret W (2008) Partial oxidation and oxidative polymerization of metallothionein. Electrophoresis 29:4169–4176. doi: 10.1002/elps.200700922 PubMedCrossRefGoogle Scholar
  30. Hao Q, Maret W (2005) Imbalance between pro-oxidant and pro-antioxidant functions of zinc in disease. J Alzheimer’s Dis 8:161–170Google Scholar
  31. Hao Q, Maret W (2006) Aldehydes release zinc from proteins. A pathway from oxidative stress/lipid peroxidation to cellular functions of zinc. FEBS J 273:4300–4310. doi: 10.1111/j.1742-4658.2006.05428.x PubMedCrossRefGoogle Scholar
  32. Hao Q, Hong S-H, Maret W (2007) Lipid raft-dependent endocytosis of metallothionein in HepG2 cells. J Cell Physiol 210:428–435. doi: 10.1002/jcp.20874 PubMedCrossRefGoogle Scholar
  33. Heinz U, Kiefer M, Tholey A et al (2005) On the competition for available zinc. J Biol Chem 280:3197–3207. doi: 10.1074/jbc.M409425200 PubMedCrossRefGoogle Scholar
  34. Hennig B, Meerarani P, Toborek M et al (1999) Antioxidant-like properties of zinc in activated endothelial cells. J Am Coll Nutr 18:152–158PubMedGoogle Scholar
  35. Hogstrand C, Verbost PM, Wendelaar Bonga SE (1999) Inhibition of human Ca2+-ATPase by Zn2+. Toxicology 133:139–145. doi: 10.1016/S0300-483X(99)00020-7 PubMedCrossRefGoogle Scholar
  36. Jacob C, Maret W, Vallee BL (1999) Selenium redox biochemistry of zinc/sulfur coordination sites in proteins and enzymes. Proc Natl Acad Sci USA 96:1910–1914. doi: 10.1073/pnas.96.5.1910 PubMedCrossRefGoogle Scholar
  37. Kägi JHR (1993) Evolution, structure and chemical activity of class I metallothioneins: an overview. In: Suzuki KT, Imura N, Kimura M (eds) Metallothionein III. Biological roles and medical implications. Birkhäuser, BaselGoogle Scholar
  38. Krężel A, Maret W (2006) Zinc buffering capacity of a eukaryotic cell at physiological pZn. J Biol Inorg Chem 11:1049–1062. doi: 10.1007/s00775-006-0150-5 PubMedCrossRefGoogle Scholar
  39. Krężel A, Maret W (2007a) The nanomolar and picomolar zinc binding properties of metallothionein. J Am Chem Soc 129:10911–10921. doi: 10.1021/ja071979s PubMedCrossRefGoogle Scholar
  40. Krężel A, Maret W (2007b) Different redox states of metallothionein/thionein in biological tissue. Biochem J 402:551–558. doi: 10.1042/BJ20061044 PubMedCrossRefGoogle Scholar
  41. Krężel A, Maret W (2008) Thionein/metallothionein control Zn(II) availability and the activity of enzymes. J Biol Inorg Chem 13:401–409. doi: 10.1007/s00775-007-0330-y PubMedCrossRefGoogle Scholar
  42. Krężel 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 463:188–200. doi: 10.1016/j.abb.2007.02.017 PubMedCrossRefGoogle Scholar
  43. Kröncke K-D, Fehsel K, Schmid T et al (1994) Nitric oxide destroys zinc-sulfur clusters inducing zinc release from metallothionein and inhibition of the zinc finger-type yeast transcription factor LAC9. Biochem Biophys Res Commun 200:1105–1110. doi: 10.1006/bbrc.1994.1564 PubMedCrossRefGoogle Scholar
  44. Laity JH, Andrews GK (2007) Understanding the mechanism of zinc-sensing by metal-response element binding transcription factor-1 (MTF-1). Arch Biochem Biophys 463:201–210. doi: 10.1016/j.abb.2007.03.019 PubMedCrossRefGoogle Scholar
  45. Li Y, Maret W (2008) Human metallothionein metallomics. J Anal At Spectrom 23:1055–1062. doi: 10.1039/b802220h CrossRefGoogle Scholar
  46. Lu M, Fu D (2007) Structure of the zinc transporter Yiip. Science 317:1746–1748. doi: 10.1126/science.1143748 PubMedCrossRefGoogle Scholar
  47. Maret W (1994) Oxidative metal release from metallothionein via zinc-thiol/disulfide interchange. Proc Natl Acad Sci USA 91:237–241. doi: 10.1073/pnas.91.1.237 PubMedCrossRefGoogle Scholar
  48. Maret W (2000) The function of zinc metallothionein: a link between cellular zinc and redox state. J Nutr 130:1455S–1458SPubMedGoogle Scholar
  49. Maret W (2003) The cellular zinc and redox states converge in the metallothionein/thionein pair. J Nutr 133:1460S–1462SPubMedGoogle Scholar
  50. Maret W (2004a) Exploring the zinc proteome. J Anal At Spectrom 19:15–19. doi: 10.1039/b307540k CrossRefGoogle Scholar
  51. Maret W (2004b) 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, Cygler M (eds) Handbook of metalloproteins, vol 3. Wiley, ChichesterGoogle Scholar
  52. Maret W (2004c) Zinc and sulfur: a critical biological partnership. Biochemistry 43:3301–3309. doi: 10.1021/bi036340p PubMedCrossRefGoogle Scholar
  53. Maret W (2005) Zinc coordination environments in proteins determine zinc functions. J Trace Elem Med Biol 19:7–12. doi: 10.1016/j.jtemb.2005.02.003 PubMedCrossRefGoogle Scholar
  54. Maret W (2006) Zinc coordination environments in proteins as redox sensors and signal transducers. Antioxid Redox Signal 8:1419–1441. doi: 10.1089/ars.2006.8.1419 PubMedCrossRefGoogle Scholar
  55. Maret W (2008a) Zinc proteomics and the annotation of the human zinc proteome. Pure Appl Chem 80:2679–2687CrossRefGoogle Scholar
  56. Maret W (2008b) Metallothionein redox biology in the cytoprotective and cytotoxic functions of zinc. Exp Gerontol 43:363–369. doi: 10.1016/j.exger.2007.11.005 PubMedCrossRefGoogle Scholar
  57. Maret W (2008c) Thiol reactivity as a central aspect of metallothionein’s mechanism of action. In: Zatta P (ed) Metallothioneins in biochemistry and pathology. World Scientific Publishing Co., SingaporeGoogle Scholar
  58. Maret W, Krężel A (2007) Cellular zinc and redox buffering capacity of metallothionein/thionein in health and disease. Mol Med 13:371–375. doi: 10.2119/2007-00036.Maret PubMedCrossRefGoogle Scholar
  59. Maret W, Vallee BL (1998) Thiolate ligands in metallothionein confer redox activity on zinc clusters. Proc Natl Acad Sci USA 95:3478–3482. doi: 10.1073/pnas.95.7.3478 PubMedCrossRefGoogle Scholar
  60. Maret W, Larsen KS, Vallee BL (1997) Coordination dynamics of biological zinc “clusters” in metallothioneins and in the DNA-binding domain of the transcription factor Gal4. Proc Natl Acad Sci USA 94:2233–2237. doi: 10.1073/pnas.94.6.2233 PubMedCrossRefGoogle Scholar
  61. Maret W, Jacob C, Vallee BL et al (1999) Inhibitory sites in enzymes: zinc removal and reactivation by thionein. Proc Natl Acad Sci USA 96:1936–1940. doi: 10.1073/pnas.96.5.1936 PubMedCrossRefGoogle Scholar
  62. Nies DH (2007) How cells control zinc homeostasis. Science 317:1695–1696. doi: 10.1126/science.1149048 PubMedCrossRefGoogle Scholar
  63. O’Halloran TV, Culotta VC (2000) Metallochaperones, an intracellular shuttle service for metal ions. J Biol Chem 275:25057–25060. doi: 10.1074/jbc.R000006200 PubMedCrossRefGoogle Scholar
  64. Oteiza PI, Olin KL, Fraga CG et al (1995) Zinc deficiency causes oxidative damage to proteins, lipids and DNA in rat testes. J Nutr 125:823–829PubMedGoogle Scholar
  65. Otvos JD, Liu X, Li H (1993) Dynamic aspects of metallothionein structure. In: Suzuki KT, Imura N, Kimura M (eds) Metallothionein III. Biological roles and medical implications. Birkhäuser, BaselGoogle Scholar
  66. Outten CE, O’Halloran TV (2001) Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science 292:2488–2492. doi: 10.1126/science.1060331 PubMedCrossRefGoogle Scholar
  67. Pearce LL, Gandley RE, Han W et al (2000) Role of metallothionein in nitric oxide signaling as revealed by a green fluorescent fusion protein. Proc Natl Acad Sci USA 97:477–482. doi: 10.1073/pnas.97.1.477 PubMedCrossRefGoogle Scholar
  68. Peck EJ Jr, Ray WJ Jr (1971) Metal complexes of phosphoglucomutase in vivo. J Biol Chem 246:1160–1167PubMedGoogle Scholar
  69. Potter BM, Feng LS, Parasuram P et al (2005) The six fingers of metal-responsive element binding transcription factor-1 form stable and quasi-ordered structures with relatively small differences in zinc affinities. J Biol Chem 280:28529–28540. doi: 10.1074/jbc.M505217200 PubMedCrossRefGoogle Scholar
  70. Powell SR (2000) The antioxidant properties of zinc. J Nutr 130:1447S–1454SPubMedGoogle Scholar
  71. Robbins AH, McRee DE, Williamson M et al (1991) Refined crystal structure of Cd, Zn metallothionein at 2.0 Ǻ resolution. J Mol Biol 221:1269–1293PubMedGoogle Scholar
  72. Sensi SL, Ton-That D, Sullivan PG et al (2003) Modulation of mitochondrial function by endogenous Zn2+ pools. Proc Natl Acad Sci USA 100:6157–6162. doi: 10.1073/pnas.1031598100 PubMedCrossRefGoogle Scholar
  73. Simons TJB (1991) Intracellular free zinc and zinc buffering in human red blood cells. J Membr Biol 123:63–71. doi: 10.1007/BF01993964 PubMedCrossRefGoogle Scholar
  74. Smith PJ, Wiltshire M, Davies S et al (2002) DNA damage-induced [Zn(2+)](i) transients: correlation with cell cycle arrest and apoptosis in lymphoma cells. Am J Physiol Cell Physiol 283:C609–C622PubMedGoogle Scholar
  75. Spahl DU, Berendji-Grün D, Suschek CV et al (2003) Regulation of zinc homeostasis by inducible NO synthase-derived NO: nuclear metallothionein translocation and intranuclear Zn2+ release. Proc Natl Acad Sci USA 100:13952–13957. doi: 10.1073/pnas.2335190100 PubMedCrossRefGoogle Scholar
  76. St. Croix CM, Wasserloos KJ, Dineley KE et al (2002) Nitric oxide-induced changes in intracellular zinc homeostasis are mediated by metallothionein/thionein. Am J Physiol Lung Cell Mol Physiol 282:L185–L192PubMedGoogle Scholar
  77. Stitt MS, Wasserloos KJ, Tang X et al (2005) Nitric oxide-induced nuclear translocation of the metal responsive transcription factor, MTF-1 is mediated by zinc release from metallothionein. Vascul Pharmacol 44:149–155. doi: 10.1016/j.vph.2005.10.004 CrossRefGoogle Scholar
  78. Thomas RC, Coles JA, Deitmer JW (1991) Homeostatic muffling. Nature 350:564. doi: 10.1038/350564b0 PubMedCrossRefGoogle Scholar
  79. Tsujikawa K, Imai K, Katutani M et al (1991) Localization of metallothionein in nuclei of growing primary cultured adult rat hepatocytes. FEBS Lett 283:239–242. doi: 10.1016/0014-5793(91)80597-V PubMedCrossRefGoogle Scholar
  80. Turan B, Fliss H, Desilets M (1997) Oxidants increase intracellular free Zn2+ concentration in rabbit ventricular myocytes. Am J Physiol 272:H2106–H2905Google Scholar
  81. Vallee BL, Auld DS (1990) Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry 29:5647–5659. doi: 10.1021/bi00476a001 PubMedCrossRefGoogle Scholar
  82. Vallee BL, Maret W (1993) The functional potential and the potential functions of metallothioneins: a personal perspective. In: Suzuki KT, Imura N, Kimura M (eds) Metallothionein III. Biological roles and medical implications. Birkhäuser, BaselGoogle Scholar
  83. Williams RJP, da Silva JJRF (2000) The distribution of elements in cells. Coord Chem Rev 200–202:247–348. doi: 10.1016/S0010-8545(00)00324-6 CrossRefGoogle Scholar
  84. Yamasaki S, Sakata-Sogawa K, Hasegawa A et al (2007) Zinc is a novel intracellular second messenger. J Cell Biol 177:637–645. doi: 10.1083/jcb.200702081 PubMedCrossRefGoogle Scholar
  85. Yang Y, Maret W, Vallee BL (2001) Differential fluorescence labeling of cysteinyl clusters uncovers high tissue levels of thionein. Proc Natl Acad Sci USA 98:5556–5559. doi: 10.1073/pnas.101123298 PubMedCrossRefGoogle Scholar
  86. Ye B, Maret W, Vallee BL (2001) Zinc metallothionein imported into liver mitochondria modulates respiration. Proc Natl Acad Sci USA 98:2317–2322. doi: 10.1073/pnas.041619198 PubMedCrossRefGoogle Scholar
  87. Zhang X, Tamaru H, Khan SI et al (2002) Structure of neurospora SET domain protein DIM-5, a histone H3 lysine methyltransferase. Cell 111:117–127. doi: 10.1016/S0092-8674(02)00999-6 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

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

Personalised recommendations