, Volume 14, Issue 2, pp 99–112 | Cite as

Old Iron, Young Copper: from Mars to Venus

  • R.R. Crichton
  • J.-L. Pierre


Iron and copper are metals which play an important role in the living world. From a brief consideration of their chemistry and biochemistry we conclude that the early chemistry of life used water soluble ferrous iron while copper was in the water-insoluble Cu(I) state as highly insoluble sulphides. The advent of oxygen was a catastrophic event for most living organisms, and can be considered to be the first general irreversible pollution of the earth. In contrast to the oxidation of iron and its loss of bioavailability as insoluble Fe(III), the oxidation of insoluble Cu(I) led to soluble Cu(II). A new iron biochemistry became possible after the advent of oxygen, with the development of chelators of Fe(III), which rendered iron once again accessible, and with the control of the potential toxicity of iron by its storage in a water soluble, non-toxic, bio-available storage protein (ferritin). Biology also discovered that whereas enzymes involved in anaerobic metabolism were designed to operate in the lower portion of the redox spectrum, the arrival of dioxygen created the need for a new redox active metal which could attain higher redox potentials. Copper, now bioavailable, was ideally suited to exploit the oxidizing power of dioxygen. The arrival of copper also coincided with the development of multicellular organisms which had extracellular cross-linked matrices capable of resisting attack by oxygen free radicals. After the initial `iron age' subsequent evolution moved, not towards a `copper age', but rather to an `iron-copper' age. In the second part of the review, this symbiosis of iron and copper is examined in yeast. We then briefly consider iron and copper metabolism in mammals, before looking at iron-copper interactions in mammals, particularly man, and conclude with the reflection that, as in Greek and Roman mythology, a better understanding of the potentially positive interactions between Mars (iron) and Venus (copper) can only be to the advantage of our species.


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  1. Askwith C, Eide D, Van Ho A et al. 1994 The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell 76, 403–410.Google Scholar
  2. Askwith C, Kaplan J. 1998 Iron and copper transport in yeast and its relevance to human disease. Trends Biochem Sci 23, 135–138.Google Scholar
  3. Baker EN. 1997 Iron(ic) twists of fate [news]. Nature Struct Biol 4, 869–871.Google Scholar
  4. Bruns CM, Nowalk AJ, Arvai AS et al. 1997 Structure of Haemophilus influenzae Fe(+3)-binding protein reveals convergent evolution within a superfamily. Nature Struct Biol 4, 919–924.Google Scholar
  5. Crichton RR. 1991 Inorganic Biochemistry of Iron Metabolism. Chichester: Ellis Horwood, pp 263.Google Scholar
  6. Dancis A, Yuan DS, Halle D et al. 1994 Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport. Cell 76, 393–402.Google Scholar
  7. De Silva DM, Askwith CC, Kaplan J. 1996 Molecular mechanisms of iron uptake in eukaryotes. Physiol Rev 76, 31–47.Google Scholar
  8. Frausto da Silva JJR, Williams RJP. 1991 The Biological Chemistry of the Elements. Oxford: Clarendon-Press.Google Scholar
  9. Frolow F, Kalb (Gilbao) AJ, Yariv J. 1994 Structure of a unique twofold symmetric haem-binding site. Nature Struct Biol 1, 453–460.Google Scholar
  10. Gamonet F, Loaquin GJM. 1998 The Saccharomyces cerevisiae LYS7 gene is involved in oxidative stress protection. Eur J Biochem 251, 716–723.Google Scholar
  11. Glerum DM, Koerner TJ, Tzagaloff A. 1996a Cloning and characterization of COX14, whose product is required for assembly of yeast cytochrome oxidase. J Biol Chem 271, 14504–14509.Google Scholar
  12. Glerum DM, Shtanko A, Tzagaloff A. 1996b SCO1 and SCO2 act as high copy suppressors of a mitochondrial copper recruitment defect in Saccharomyces cerevisiae. J Biol Chem 271, 20531–20535.Google Scholar
  13. Gubler CJ, Cartwright GE, Wintrobe MM. 1956 Studies on copper metabolism XX Enzyme activities and iron metabolism in copper and iron deficiencies. J Biol Chem 224, 533–546.Google Scholar
  14. Gunshin H, Mackenzie B, Berger UV et al. 1997 Cloning and characterization of amammalian proton-coupled metal-ion transporter. Nature 388, 482–488.Google Scholar
  15. Hamza I, Schaefer M, Klomp LWJ et al. 1999 Interaction of the copper chaperone HAH1 with the Wilson disease protein is essential for copper homeostasis. Proc Natl Acad Sci USA 96, 13363–13368.Google Scholar
  16. Harris ZL, Takahashi T, Miyajima H et al. 1995 Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci USA 92, 2539–2543.Google Scholar
  17. Harris JL, Durley AP, Man TK et al. 1999 Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci USA 96, 10812–10817.Google Scholar
  18. Harrison MD, Jones CE, Dameron CT. 1999 Copper chaperones: function, structure and copper-binding properties. J Biol Inorg Chem 4, 145–153.Google Scholar
  19. Harrison MD, Jones CE, Solioz M et al. 2000 Intracellular copper routing: the role of copper chaperones. Trends Biochem Sci 25, 29–32.Google Scholar
  20. Hart EB, Steenbock H, Waddell J et al. 1928 Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin building in the rat. J Biol Chem 77, 797–812.Google Scholar
  21. Holm RH, Kennepohl P, Solomon EI. 1996 Structural and functional aspects of metal sites in biology. Chem Rev 96, 2239–2314.Google Scholar
  22. Hempstead PD, Hudson AJ, Artymuik PJ et al. 1994 Direct observation of the iron binding sites in a ferritin. FEBS Letts 350, 258–262.Google Scholar
  23. Horecka J, Kinsey PT, Sprague JF. 1995 Cloning and characterization of the Saccharomyces cerevisiae LYS7 gene: evidence for function outside of lysine biosynthesis. Gene 162, 716–723.Google Scholar
  24. Huber C, Wächtershauser G. 1997 Activated acetic acid by carbon fixation on (Fe,Ni)S under primordial conditions. Science 276, 245–247 and ref. cited therein.Google Scholar
  25. Huheey HE, Keiter EA, Keiter RL. 1993 Inorganic Chemistry. New-York: Harper Collins College Publishers.Google Scholar
  26. Jensen LT, Howard WR, Strain JJ et al. 1996 Enhanced effectiveness of copper ion buffering by CUP1 metallothionein compared with CRS5 metallothionein in Saccharomyces cerevisiae. J Biol Chem 271, 18514–18519.Google Scholar
  27. Johnson PJ. 1995 Acute and chronic liver disease. In: Marshall WJ, Bangert SK, eds. Clinical Biochemistry Metabolic and Clinical Aspects. New York: Churchill Livingstone; pp. 237–256.Google Scholar
  28. Kaim W, Rall J. 1996 Copper-a ‘modern’ bioelement. Angew Chem Int Ed Engl 35, 43–60.Google Scholar
  29. Kampfenkel K, Kushnir S, Baviychuk E et al. (1995) Molecular characterization of a putative Arabidopsis thaliana copper transporter and its yeast homologue. J Biol Chem 270, 28479–28486.Google Scholar
  30. Klinman JP. 1996 Mechanism whereby mononuclear copper proteins functionalize organic substrates. Chem Rev 96, 2541–2561.Google Scholar
  31. Klomp LW, Gitlin JD. 1997 Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemia. Hum Mol Genet 5, 1989–1996.Google Scholar
  32. Klomp LWJ, Lin SJ, Yuan DS et al. 1997 Identification and functional expression of HAH1, a novel gene involved in copper homeostasis. J Biol Chem 272, 9221–9226.Google Scholar
  33. Knight SA, Labbe S, Kwon LF et al. 1996 A widespread transposable element masks expression of a yeast copper transport gene. Genes Dev 10, 1917–1929.Google Scholar
  34. Koch KA, Pena MM, Thiele DJ. 1997 Copper-binding motifs in catalysis, transport, detoxification and signaling. Chem & Biol 4, 549–560.Google Scholar
  35. Konhauser KO. 1997 Bacterial iron biomineralisation in nature. FEMS Microbiol Rev 20, 315–326.Google Scholar
  36. Kossman DJ, Hassett R, McCracken J. 1998 Spectroscopic characterization of the Cu(II) sites in the Fet3 protein, the multinuclear copper oxidase from yeast required for high-affinity iron uptake. J Am Chem Soc 120, 4037–4038.Google Scholar
  37. Lee GR, Nacht S, Lukens JN et al. 1968 Iron metabolism in copperdeficient swine. J Clin Invest 47, 2058–2069.Google Scholar
  38. Lesuisse E, Raguzzi F, Crichton RR. 1987 Iron uptake by the yeast Saccharomyces cerevisieae: involvement of a reduction step. J Gen Microbiol 133, 3229–3236.Google Scholar
  39. Lin SJ, Pufahl RA, O'Halloran TV et al. 1997 A role for the Saccharomyces cerevisiae ATX1 gene in copper trafficking and iron transport. J Biol Chem 272, 9215–9220.Google Scholar
  40. Lippard SJ, Berg JM. 1994 Principles of Bioinorganic Chemistry. Mill Valley: University Science Books.Google Scholar
  41. Liu XD, Thiele DJ. 1997 Yeast metallothionein gene expression in response to metals and oxidative stress. Methods 11, 289–299.Google Scholar
  42. Mann S. 1997 Biomineralization: the form(id)able part of bioinorganic chemistry. J Chem Soc Dalton, 3953–3961.Google Scholar
  43. Maurel MC, Décout JL. 1999 Origins of life: molecular foundations and new approaches. Tetrahedron 55, 3141–3182.Google Scholar
  44. Mukhopadhyay CK, Attieh ZK, Fox PL. 1998 Role of ceruloplasmin in cellular iron uptake. Science 279, 714–717.Google Scholar
  45. Mukhopadhyay CK, Mazumder B, Fox PL. 2000 Role of hypoxiainducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J Biol Chem 275, 21048–21054.Google Scholar
  46. Nagano K, Nakamura K, Urakami KI et al. 1998 Intracellular distribution of the Wilson's disease gene product (ATPase7B) after in vitro and in vivo exogenous expression in hepatocytes from the LEC rat, an animal model of Wilson's disease. Hepatology 27, 799–807.Google Scholar
  47. Olivares M, Uauy R. 1996 Copper as an essential nutrient. Am J Clin Nutr 63, 791S-796S.Google Scholar
  48. Orchiai EI. 1986 Iron versus copper II. Principles and applications in bioinorganic chemistry. J Chem Educ 63, 942–944.Google Scholar
  49. Osaki S, Johnson DA, Frieden E. 1966 The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem 241, 2476–2451.Google Scholar
  50. Pena MM, Koch KA, Thiele FJ. 1998 Dynamic regulation of copper uptake and detoxification genes in Saccharomyces cerevisiae. Mol Cell Biol 18, 2514–2523.Google Scholar
  51. Petris MJ, Mercer JF, Culvenor JG et al. 1996 Ligand-regulated transportof the Menkes copper P-type ATPase efflux from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking. EMBO J 15, 6084–6095.Google Scholar
  52. Pountney DL, Schauwecker I, Zarn J et al. 1994 Formation of mammalian Cu8-metallothionein in vitro: evidence for the existence of two Cu(I) 4-thiolate clusters. Biochem 33, 9699–9715.Google Scholar
  53. Pufahl RA, Singer CP, Peariso KL et al. 1997 Metal ion chaperone function of the soluble Cu(I) receptor Atx1. Science 278, 853–856.Google Scholar
  54. Que L, Ho RYN. 1996 Dioxygen activation by enzymes with mononuclear non-heme iron active sites. Chem Rev 96, 2607–2624.Google Scholar
  55. Ragan HA, Nacht S, Lee GR et al. 1969 Effect of ceruloplasmin on plasma iron in copper-deficient swine. Am J Physiol 217, 1320–1323.Google Scholar
  56. Raguzzi F, Lesuisse E, Crichton RR. 1988 Iron storage in Saccharomyces cerevisiae. FEBS Letts 231, 253–258.Google Scholar
  57. Salomon EI, Sundaram UM, Machonkin TE. 1996 Multicopper oxidases and oxygenases. Chem Rev 96, 2563–2605.Google Scholar
  58. Sato M, Gitlin JD. 1991 Mechanisms of copper incorporation during the biosynthesis of human ceruloplasmin. J Biol Chem 266, 5128–5134.Google Scholar
  59. Scheinberg IH, Gitlin JD. 1952 Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson's disease). Science 116, 484–485.Google Scholar
  60. Sigel A, Sigel H. eds 1998 Iron transport and storage in microorganisms, plants and animals. Metal ions in biological systems 35, pp. 775.Google Scholar
  61. Sono M, Roach MP, Coulter ED, Dawson JH. 1996 Hemecontaining oxygenases. Chem Rev 96, 2841–2887.Google Scholar
  62. Stearman R, Yuan DS, Yamaguchi-Iwai Y et al. 1996 A permeaseoxidase complex involved in high-affinity iron uptake in yeast. Science 271, 1552–1557.Google Scholar
  63. Strain J, Culotta VC. 1996 Copper ions and the regulation of Saccharomyces cerevisiae metallothionein genes under aerobic and anaerobic conditions. Mol Gen Genet 251, 139–145.Google Scholar
  64. Vasak M, Hasler DW. 2000 Metallothioneins-new functional and structural insights. Curr Opin Chem Biol 4, 177–183.Google Scholar
  65. Vulpe CD, Kuo YM, Murphy TL et al. 1999 Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 21, 195–199.Google Scholar
  66. Wallar BJ, Lipscomb JD. 1996 Dioxygen activation by enzymes containing binuclear non heme iron clusters. Chem Rev 96, 2625–2657.Google Scholar
  67. Ward RJ, Scarino L, Leone A et al. 1998 Copper and iron homeostasis in mammalian cells and cell lines. Biochem Soc Trans 26, S191.Google Scholar
  68. Williams DM, Lee GR, Cartwright GE. 1974 Ferroxidase activity of rat ceruloplasmin. Am J Physiol 227, 1094–1097.Google Scholar
  69. Williams DM, Loukopoulus D, Lee GR et al. 1976 Interference with copper metabolism. Blood 48, 77–85.Google Scholar
  70. Yoshida K, Furihata K, Takeda S et al. 1995 A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nature Genet 9, 267–272.Google Scholar
  71. Yuan DS, Stearman R, Dancis A et al. 1995 The Menkes/Wilson disease homologue in yeast provides copper to a ceruloplasminlike oxidase required for iron uptake. Proc Natl Acad Sci USA 92, 2632–2636.Google Scholar
  72. Zhou B, Gitscher J. 1997 HCTR1: a human gene for human copper uptake identified by complementation of yeast. Proc Natl Acad Sci USA 94, 7481–7486.Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • R.R. Crichton
    • 1
  • J.-L. Pierre
    • 2
  1. 1.Unité de BiochimieUniversité Catholique de LouvainLouvain-la-NeuveBelgium
  2. 2.Laboratoire de Chimie Biomimétique (LEDSS, UMR CNRS 5616)Université J. Fourier BP 53France

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