Hostname: page-component-745bb68f8f-grxwn Total loading time: 0 Render date: 2025-01-27T19:09:23.416Z Has data issue: false hasContentIssue false
  • English
  • Français

The molecular basis of copper and iron interactions

Published online by Cambridge University Press:  07 March 2007

Paul Sharp
Paul Sharp*
Affiliation:
Centre for Nutrition and Food Safety, School of Biomedical and Molecular Sciences, University of Surrey,Guildford, GU2 7XH, UK
*
Corresponding author: Dr Paul Sharp, fax +44 1483 576978, email p.sharp@surrey.ac.uk
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The intimate relationship between Fe and Cu in human nutrition has been recognised for many years. The best-characterised link is provided by caeruloplasmin, a multiCu-binding protein that acts as a serum ferrioxidase and is essential for the mobilisation of Fe from storage tissues. Decreased Cu status has been shown to reduce holo-caeruloplasmin production and impair ferrioxidase activity, leading, in a number of cases, to decreased tissue Fe release and the generation of anaemia that is responsive to dietary supplementation with Cu but not Fe. Dietary Fe absorption also requires the presence of a multiCu ferrioxidase. Hephaestin, a caeruloplasmin homologue, works in concert with the IREG1 transporter to permit Fe efflux from enterocytes for loading onto transferrin. The essential role of hephaestin in this process has been recognised from studies in the sex-linked anaemic (sla) mouse, in which Fe efflux is markedly impaired as a result of a mutation in the hephaestin gene that results in a truncated and non-functional version of the protein. There is emerging evidence that a number of other components of the intestinal Fe transport pathway are also Cu sensitive. Divalent metal transporter 1 (DMT1), the Fe transporter located at the apical membrane of enterocytes, is also a physiologically-relevant Cu transporter, suggesting that these two metals may compete with each other for uptake into the duodenal enterocytes. Furthermore, expression of both DMT1 and the basolateral Fe-efflux transporter IREG1 can be regulated by Cu, suggesting that the Fe–Cu relationship may be more complex than first thought.

Keywords

CuFeAnaemiaCaeruloplasminDMT1
Type
Symposium on ‘Micronutrient interactions and public health’
Information
Proceedings of the Nutrition Society , Volume 63 , Issue 4 , November 2004 , pp. 563 - 569
Copyright
Copyright © The Nutrition Society 2004

References

Abboud, S & Haile, DJ (2000) A novel mammalian iron-regulated protein involved in intracellular iron metabolism. Journal of Biological Chemistry 275, 19906–19912.CrossRefGoogle ScholarPubMed
Anderson, GJ, Murphy, TL, Cowley, L, Evans, BA, Halliday, JW & McLaren, GD (1998) Mapping the gene for sex-linked anemia: an inherited defect of intestinal iron absorption in the mouse. Genomics 48, 34–39.CrossRefGoogle ScholarPubMed
Andrews, NC (1999) Disorders of iron metabolism. New England Journal of Medicine 341, 1986–1995.CrossRefGoogle ScholarPubMed
Andrews, NC (2000) Iron homeostasis: insights from genetics and animal models. Nature Reviews Genetics 1, 208–217.CrossRefGoogle ScholarPubMed
Arredondo, M, Munoz, P, Mura, CV & Nunez, MT (2003) DMT1, a physiologically relevant apical Cu1+ transporter of intestinal cells. American Journal of Physiology 284, C1525–C1530.CrossRefGoogle ScholarPubMed
Askwith, C, Eide, D, Van Ho, A, Bernard, PS, Li, L, Davis-Kaplan, S, Sipe, DM & Kaplan, J (1994) The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell 76, 403–410.CrossRefGoogle ScholarPubMed
Attieh, ZK, Alaeddine, RM, Su, T, Anderson, GJ & Vulpe, C (2002) Identification of a ferroxidase activity of hephaestin. Journal of Clinical Gastroenterology 34, 370.Google Scholar
Bonham, M, O'Connor, JM, Hannigan, BM & Strain, JJ (2002) The immune system as a physiological indicator of marginal copper status. British Journal of Nutrition 87, 393–403.CrossRefGoogle ScholarPubMed
Cartwright, GE, Gubler, CJ, Bush, JA & Wintrobe, MM (1956) Studies of copper metabolism. XVII. Further observations on the anemia of copper deficiency in swine. Blood 11, 143–153.CrossRefGoogle ScholarPubMed
Coppen, DE & Davies, NT (1988) Studies on the roles of apotransferrin and caeruloplasmin ( EC 1.16.3.1) on iron absorption in copper-deficient rats using an isolated vascularly- and luminally-perfused intestinal preparation. British Journal of Nutrition 60, 361–373.CrossRefGoogle ScholarPubMed
Cordano, A, Baertl, JM & Graham, GG (1964) Copper deficiency in infancy. Pediatrics 34, 324–336.CrossRefGoogle ScholarPubMed
Curzon, G, O'Reilly, S (1960) A couple iron-caeruloplasmin oxidation system. Biochemical and Biophysical Research Communications 2, 284–286.CrossRefGoogle Scholar
Dancis, A, Yuan, DS, Haile, D, Askwith, C, Eide, D, Moehle, C, Kaplan, J & Klausner, RD (1994) Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport. Cell 76, 393–402.CrossRefGoogle Scholar
Department of HealthDepartment of Health (1991) Dietary Reference Values for Food Energy and Nutrients for the United Kingdom. Report on Health and Social Subjects no.41. London: H. M. Stationery Office.Google Scholar
Donovan, A, Brownlie, A, Zhou, Y, Shepard, J, Pratt, SJ, Moynihan, J et al. (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403, 777–781.CrossRefGoogle ScholarPubMed
Faila, M (1999) Considerations for determining ‘optimal nutrition’ for copper, zinc, manganese and molybdenum. Proceedings of the Nutrition Society 58, 497–505.CrossRefGoogle Scholar
Fairweather-Tait, SJ (2004) Iron nutrition in the UK: getting the balance right. Proceedings of the Nutrition Society 63, 519–528.CrossRefGoogle ScholarPubMed
Fleming, MD, Trenor, CC, Su, MA, Foernzler, D, Beier, DR, Dietrich, WF & Andrews, NC (1997) Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nature Genetics 16, 383–386.CrossRefGoogle ScholarPubMed
Fox, PL (2003) The copper-iron chronicles: The story of an intimate relationship. BioMetals 16, 9–40.CrossRefGoogle ScholarPubMed
Frazer, DM, Vulpe, CD, McKie, AT, Wilkins, SJ, Trinder, D, Cleghorn, GJ & Anderson, GJ (2001) Cloning and gastrointestinal expression of rat hephaestin: relationship to other iron transport proteins. American Journal of Physiology 281, G931–G939.Google ScholarPubMed
Gambling, L & McArdle, HJ (2004) Iron, copper and fetal development. Proceedings of the Nutrition Society 63, 553–562.CrossRefGoogle ScholarPubMed
Gunshin, H, Mackenzie, B, Berger, UV, Gunshin, Y, Romero, MF, Boron, WF, Nussberger, S, Gollan, JL & Hediger, MA (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388, 482–487.CrossRefGoogle ScholarPubMed
Hallberg, L (1981) Bioavailability of dietary iron in man. Annual Review of Nutrition 1, 123–147.CrossRefGoogle ScholarPubMed
Harris, ZL, Durley, AP, Man, TK & Gitlin, JD (1999) Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proceedings of the National Academy of Sciences USA 96, 10812–10817.CrossRefGoogle ScholarPubMed
Harris, ZL, Klomp, LW & Gitlin, JD (1998) Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. American Journal of Clinical Nutrition 67, 972S–977S.CrossRefGoogle ScholarPubMed
Hart, EB, Steenbock, H, Waddell, J & Elvehjem, CA (1928) Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin building in the rat. Journal of Biological Chemistry 77, 797–812.CrossRefGoogle Scholar
Holmberg, CG, Laurell, C-B (1948) Investigations in serum copper. II. Isolation of the copper containing protein and a description of some of its properties. Acta Chemica Scandinavia 2, 550–556.CrossRefGoogle Scholar
Kehoe, CA, Turley, E, Bonham, MP, O'Connor, JM, McKeown, A, Faughnan, MS, Coulter, JS, Gilmore, WS, Howard, AN & Strain, JJ (2000) Response of putative indices of copper status to copper supplementation in human subjects. British Journal of Nutrition 84, 151–156.CrossRefGoogle ScholarPubMed
Klomp, AE, Tops, BB, Van Denberg, IE, Berger, R, Klomp, LW (2002) Biochemical characterization and subcellular localization of human copper transporter 1 (hCTR1). Biochemical Journal 364, 497–505.CrossRefGoogle ScholarPubMed
Knopfel, M & Solioz, M (2002) Characterization of a cytochrome b(558) ferric/cupric reductase from rabbit duodenal brush border membranes. Biochemical and Biophysical Research Communications 291, 220–225.CrossRefGoogle ScholarPubMed
Kuo, YM, Zhou, B, Cosco, D & Gitschier, J (2001) The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proceedings of the National Academy of Sciences USA 98, 6836–6841.CrossRefGoogle ScholarPubMed
Lee, GR, Nacht, S, Lukens, JN & Cartwright, GE (1968) Iron metabolism in copper-deficient swine. Journal of Clinical Investigation 47, 2058–2069.CrossRefGoogle ScholarPubMed
Lee, J, Peña, MM, Nose, Y & Thiele, DJ (2002) Biochemical characterization of the human copper transporter Ctr1. Journal of Biological Chemistry 277, 4380–4387.CrossRefGoogle ScholarPubMed
Lee, J, Prohaska, JR, Dagenais, SL, Glover, TW & Thiele, DJ (2000) Isolation of a murine copper transporter gene, tissue specific expression and functional complementation of a yeast copper transport mutant. Gene 254, 87–96.CrossRefGoogle ScholarPubMed
Lee, J, Prohaska, JR & Thiele, DJ (2001) Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. Proceedings of the National Academy of Sciences USA 98, 6842–6847.CrossRefGoogle ScholarPubMed
Lee, PL, Gelbart, T, West, C, Halloran, C & Beutler, E (1998) The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells and Molecular Diseases 24, 199–215.CrossRefGoogle ScholarPubMed
Levy, Y, Zeharia, A, Grunebaum, M, Nitzan, M & Steinherz, R (1985) Copper deficiency in infants fed cow milk. Journal of Pediatrics 106, 786–788.CrossRefGoogle ScholarPubMed
Linder, MC, Hazegh-Azam, M (1996) Copper biochemistry and molecular biology. American Journal of Clinical Nutrition 63, 797S–811S.Google ScholarPubMed
Linder, MC, Zerounian, NR, Moriya, M & Malpe, R (2003) Iron and copper homeostasis and intestinal absorption using the Caco2 cell model. BioMetals 16, 145–160.CrossRefGoogle ScholarPubMed
McKie, AT, Barrow, D, Latunde-Dada, GO, Rolfs, A, Sager, G & Mudaly, E et al. 2001) An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291, 1755–1759.CrossRefGoogle ScholarPubMed
McKie, AT, Marciani, P, Rolfs, A, Brennan, K, Wehr, K & Barrow, D et al. (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Molecular Cell 5, 299–309.CrossRefGoogle ScholarPubMed
Mercer, JFB (2001) The molecular basis of copper-transport diseases. Trends in Molecular Medicine 7, 64–69.CrossRefGoogle ScholarPubMed
Milne, DB (1998) Copper intake and assessment of copper status. American Journal of Clinical Nutrition 67, 1041S–1045S.CrossRefGoogle ScholarPubMed
Miyajima, H, Nishimura, Y, Mizoguchi, K, Sakamoto, M, Shimizu, T & Honda, N (1987) Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration. Neurology 37, 761–767.CrossRefGoogle ScholarPubMed
Osaki, S & Johnson, DA (1969) Mobilization of liver iron by ferroxidase (ceruloplasmin). Journal of Biological Chemistry 244, 5757–5758.CrossRefGoogle ScholarPubMed
Osaki, S, Johnson, DA & Frieden, E (1966) The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. Journal of Biological Chemistry 241, 2746–2751.CrossRefGoogle ScholarPubMed
Oshiro, S, Nozawa, K, Hori, M, Zhang, C, Hashimoto, Y, Kitajima, S & Kawamura, K (2002) Modulation of iron regulatory protein-1 by various metals. Biochemical and Biophysical Research Communications 290, 213–218.CrossRefGoogle ScholarPubMed
Peña, MO, Lee, J & Thiele, DJ (1999) A delicate balance: Homeostatic control of copper uptake and distribution. Journal of Nutrition 129, 1251–1260.CrossRefGoogle ScholarPubMed
Petris, MJ, Smith, K, Lee, J & Thiele, DJ (2003) Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. Journal of Biological Chemistry 278, 9639–9646.CrossRefGoogle ScholarPubMed
Prohaska, JR, Tamura, T, Percy, AK & Turnlund, JR (1997) In vitro copper stimulation of plasma peptidylglycine alpha-amidating monooxygenase in Menkes disease variant with occipital horns. Pediatrics Research 42, 862–865.CrossRefGoogle ScholarPubMed
Puig, S & Thiele, DJ (2002) Molecular mechanisms of copper uptake and distribution. Current Opinions in Chemical Biology 6, 171–180.CrossRefGoogle ScholarPubMed
Rolfs, A, Bonkovsky, HL, Kohlroser, JG, McNeal, K, Sharma, A, Berger, UV & Hediger, MA (2002) Intestinal expression of genes involved in iron absorption in humans. American Journal of Physiology 282, G598–G607.Google ScholarPubMed
Sharp, PA (2003) Ctr1 and its role in body copper homeostasis. International Journal of Biochemistry and Cell Biology 35, 288–291.CrossRefGoogle ScholarPubMed
Smith, SE & Medlicott, M (1944) The blood picture of iron and copper deficiency anemias in the rat. American Journal of Physiology 141, 354–358.CrossRefGoogle Scholar
Syed, BA, Beaumont, NJ, Patel, A, Naylor, CE, Bayele, HK, Joannou, CL, Rowe, PS, Evans, RW & Srai, SK (2002) Analysis of the human hephaestin gene and protein: comparative modelling of the N-terminus ecto-domain based upon ceruloplasmin. Protein Engineering 15, 205–214.CrossRefGoogle ScholarPubMed
Tandy, S, Williams, M, Leggett, A, Lopez-Jimenez, M, Dedes, M, Ramesh, B, Srai, SK & Sharp, P (2000) Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells. Journal of Biological Chemistry 275, 1023–1029.CrossRefGoogle ScholarPubMed
Tennant, J, Stansfield, M, Yamaji, S, Srai, SK & Sharp, P (2002) Effects of copper on the expression of metal transporters in human intestinal Caco-2 cells. FEBS Letters 527, 239–244.CrossRefGoogle ScholarPubMed
Tennant, JP, Jai, T & Sharp, PA (2004) Mechanisms involved in copper uptake by human intestinal epithelial cells. Proceedings of the Nutrition Society 63, 35A.Google Scholar
Thomas, C & Oates, PS (2003) Copper deficiency increases iron absorption in the rat. American Journal of Physiology 285, G789–G795.Google ScholarPubMed
Trinder, D, Oates, PS, Thomas, C, Sadleir, J & Morgan, EH (2000) Localisation of divalent metal transporter 1 (DMT1) to the microvillus membrane of rat duodenal enterocytes in iron deficiency, but to hepatocytes in iron overload. Gut 46, 270–276.CrossRefGoogle Scholar
Turnlund, JR, Keyes, WR, Anderson, HL & Acord, LL (1989) Copper absorption and retention in young men at three levels of dietary copper by use of the stable isotope 65 Cu. American Journal of Clinical Nutrition 49, 870–878.CrossRefGoogle Scholar
Turnlund, JR, Keyes, WR, Peiffer, GL & Scott, KC (1998) Copper absorption, excretion, and retention by young men consuming low dietary copper determined by using the stable isotope 65 Cu. American Journal of Clinical Nutrition 67, 1219–1225.CrossRefGoogle Scholar
Vulpe, CD, Kuo, YM, Murphy, TL, Cowley, L, Askwith, C, Libina, N, Gitschier, J & Anderson, GJ (1999) Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nature Genetics 21, 195–199.CrossRefGoogle ScholarPubMed
Yamaji, S, Tennant, J, Sharp, P & Srai, SKS (2002) Differential regulation of divalent metal transporter (DMT1) splice variant expression by non-haem iron in human intestinal Caco-2 cells. Journal of Physiology, London 539, 20P.Google Scholar
Zerounian, NR & Linder, MC (2002) Effects of copper and ceruloplasmin on iron transport in the Caco 2 cell intestinal model. Journal of Nutritional Biochemistry 13, 138–148.CrossRefGoogle ScholarPubMed