Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지

Metal Ion Transporters Identified in Recent Studies

최근에 밝혀진 금속이온 수송체

  • Published : 2002.12.01
Download PDF
⟨ Previous Next ⟩

Abstract

The classical concept for iron uptake into mammalian cells has been the endocytosis of transferrin( $T_{f}$ )-bound F $e^{3+}$ via the $T_{f}$ - $T_{f}$ receptor cycle. In this case, we could not explain the uptake of F $e^{2＋}$ ion and the export of iron from endosome. Studies on iron transport revealed that other transport system exists in epithelial cells of the intestine. One of non- $T_{f}$ -receptor-mediated transport systems is Nramp2/DMT1/DCT1 which transports M $n^{＋＋}$, $Mg^{＋＋}$, Z $n^{＋＋}$, $Co^{＋＋}$, N $i^{＋＋}$ or C $u^{＋＋}$ ion as well as F $e^{+2}$ ion. DMT1 was cloned from intestines of iron-deficient rats and shown to be a hydrogen ion-coupled iron transporter and a protein regulated by absorbed dietary iron. DMT1 is founded in other cells such as cortical and hippocampal glial cells as well as endothelial cells in duodenum. Two F $e^{3+}$ ion bound to transferrin( $T_{f}$ ) are taken up via the $T_{f}$ - $T_{f}$ receptor cycle in the intestinal epithelial cell. F $e^{3+}$ in endosome was converted to F $e^{2＋}$ ion, and then exported to cytosol via DMT1. F $e^{2＋}$ ion is taken up into cytosol via DMT1. Several other transporters such as FET, FRE, CCC2, AFT1, SMF, FTR, ZER, ZIP, ZnT and CTR have been reported recently and dysfunction of the transporters are related with diseases containing Wilson's disease, Menkes disease and hemochromatosis. Evidences from several studies strongly suggest that DMT1 is the major transporter of iron in the intestine and functions critically in transport of other metal ions.

Keywords

References

  1. Agranoff, D.D. & Khshna, S. (1998). Metal ion homcostasis and intracellulair parasitism. Mol. Microbiol., 28, 403-412 https://doi.org/10.1046/j.1365-2958.1998.00790.x
  2. Anderson, G.J., Murphy, T.L., Cowley, L., Evans, B.A., Halliday, J.W. & McLaren, G.D. (1998). Mapping the gene for sex-linked anemia-An inherited defect of intestinal iron absorption in the mouse. Genomics, 48, 34-39 https://doi.org/10.1006/geno.1997.5138
  3. Andrews, N.C. (1999). The iron transporter DMT1.Int. J. Biochem. Cell Biol, 31, 991-994
  4. Askwith, C.C. and Kaplan, J. (1998). Iron and copper transport in yeast and its relevance to human disease. Trends in Biochemical Sciences, 23, 135-138 https://doi.org/10.1016/S0968-0004(98)01192-X
  5. Babcock, M., de Silva, D., Oaks, R., Davis-Kaplan, S., Jiralerspong, S., Montermini, L., Pandolfo, M. and Kaplan, J. (1997). Regulation of mitochondrial iron accumulation by YfhlP, a putative homolog of grataxin. Science, 276, 1709-1712 https://doi.org/10.1126/science.276.5319.1709
  6. Bannon, D.I., Portony, M.E., Olivi, L. Lees, P.S.J. Culotta, V.C., and Bressler, J.P. (2002) Uptake of lead and iron by divalent metal transporter 1 in yeast and mammalian cells. Biocheniical and Biophysical Research Communication, , 978-984 https://doi.org/10.1016/S0006-291X(02)00756-8
  7. Barton, J.C., McDonnell, S.M., Adams, P.C., Bhssot, R, Powell, L.W., Edwards, C.Q., Cook, J.D, and Kowdley, K.V. (1998). Management of hemochromatosis. Hemochromatosis Management working group. Annals of Internal Medicine, 129, 932-939 https://doi.org/10.7326/0003-4819-129-11_Part_2-199812011-00003
  8. Bellamy, R., Ruwende, C., Corrah, T., McAdam, K.P., Whittle, H.C., and Hi1l, A.V. (1998). Variations in the Nrampl gene and susceptibility to tuberculosis in West Africans. New England Journal of Medicine, , 640-644
  9. Belouchi, A., Kwan, T., and Gros, P. (1997). Cloning and characterization of the OsNramp family from Oiyza sativa, a new family of membrane proteins possibly implicated in the transport of metal ions. Plant Molecular Biotogy, 33, 1085-1092 https://doi.org/10.1023/A:1005723304911
  10. Canonne-Hergaux, Gruenheid, S. Ponka, P, and Gros, P. (1999). Cellular and subcellular localization of the Nramp2 iron transporter in the mtestinal brush border and regulation by dietary iron. Blood, 93, 4406-4417
  11. Cellier, M., Phve, G., Belouchi, A., Kwan, T., Rodngues, V, Chia, W., and Gros, P. (1995). Nramp defines a family of membrane proteins. Proc. Nati. Acad. Sci. U.S.A., 92, 10089-10093 https://doi.org/10.1073/pnas.92.22.10089
  12. Chelly, J., Tumer, Z., Tonnesen, T., Petterson, A., Ishikawa-Brush, Y., Tommerup, N., Horn, N, and Monaco, A. P. (1993). Isolation ofa candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nature Genetics, 3, 14-19 https://doi.org/10.1038/ng0193-14
  13. Chen, X.Z., Peng, J.B., Cohen, A., Nelson, H., Nelson, N, and Hediger, M.A. (1999). Yeast SMFl mediates $H^{+}$-coupled iron uptake with concomitant uncoupled cation currents. J. Biol. Chem., 274(49), 35089-35094 https://doi.org/10.1074/jbc.274.49.35089
  14. Cheong, J.H. Bannon, D.I., Olivi, L. Kim, K, and Bressler, J.P. (2002) Transport of iron and lead in a rat glial cell line. J. Neurochemistry submitted
  15. Cohen, A., Nelson, H., and Nelson, N. (2000). The family of SMF metal ion transporters in Yeast cel1s. J. Biol. Chem., 275(43), 33388-33394 https://doi.org/10.1074/jbc.M004611200
  16. Cole, T.B., wenzel, H.J., Kafei, K.E., Schwartzkroin, P.A., and Palmiter, R.D. (1999) Elimination of zinc from synaptic vesicles in fhe intact mouse braiii by disruption of the Zn T3 gene. Proc. Nati. Acad. Sci. U.S.A., 96, 1716-1721 https://doi.org/10.1073/pnas.96.4.1716
  17. Conrad, M.E., Umbreit, J.N., Peterson, R.D., Moore, E.G., and Harper, K.P. (1993). Function of integrin in duodenal mucosal optake of iron. Blood, 81, 517-521
  18. Dautry-Varsat, A., Ciechnover, A., and Lodish, H.F. (1983). Proc. Nati. Acad. Sci. U.S.A., 80, https://doi.org/10.1073/pnas.80.8.2258
  19. Dix, D.R,. Bridgham, J.T., Broderius, M.A. Byersdorfer, C.A., and Eide, D.J. (1994). The FET4 gene encodes the low affinity Fe(II). Transport protein of Saccharomyces cerevisiae. Journal of Biological Chemistry, 269, 26092-26099
  20. Dorey, C., Cooper, C., Dickson, D.R, Gibson, J.E, Simpson, R.J., and Petters, T.J. (1993). Iron spedfication at physiological pH in media containing ascorbate and oxygen. British Journal of Nutrition, 10, 157-169
  21. Edwards, J.A. and Hoke, J.H. (1972). Defect of mtestinal mucosal iron uptake in mice with hereditary microcytic anemia. Proc. Soc. Exp. Biol. Med., 141, 81-84 https://doi.org/10.3181/00379727-141-36720
  22. Eide, D.J. (1998). The molecular biology of metal ion transport in Saccharomyces cerevisiae. Annual Review of Nutrition, 18, 441-469 https://doi.org/10.1146/annurev.nutr.18.1.441
  23. Eide, D., Brodeius, M,. Fett, J., and Guerinot, M.L. (1996). A novel iron-regulated metal transportcr from plants identificd by functional expression in yeast. Proceeding of the National Academy of Sciences of fhe USA, 93, 5624-5628 https://doi.org/10.1073/pnas.93.11.5624
  24. Gac, G.L., Mura, C., Raguenes, O., Mercier, A.-Y, Braekeleer, M.D., and Ferec, M. (2000). Nramp2 analysis in hemochromatosis probands. Blood cells, Molecules, and disease, 26, 312-319 https://doi.org/10.1006/bcmd.2000.0312
  25. Farcich, E.A. and Morgan, E.H. (1992). Diminished iron acquisition by cells and tissues of Belgrade laboratory rats. Am. J. Physiol., 262, 220-224
  26. Fleming, M.D., Romano. M.A., Su, M.A., Garrick, L.M., Garrick, M.D., and Andrews, N.C.(1998). Nramp2 is mutated in the anemic belgrade (b). rat: evidence of a role for Nramp2 in endosomal iron transport, Proceedings of the National Academy of Sciences of the USA, 95, 1148-1153 https://doi.org/10.1073/pnas.95.3.1148
  27. Fleming, M.D., Trenor, C.C., Su, M.A., Foernzlei, D., Beier, D.R., Dietrich, W.E, and Andrews, N.C. (1997). Microcytic anaemia mice have mutation in Nramp2, a candidatc iron transporter gene. Nature Genetics, 16, 383-386 https://doi.org/10.1038/ng0897-383
  28. Fleming, R.E., Migas, M.C., Zhou, X., Jiang, J., Britton, R.S., Brunt, E.M., Tomatsu, S., Waheed, A., Baon, B.R., and Sly, W.S. (1999). Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: Increascd duodenal expression of the iron traspoter DMTl. Proceeding of the National Academy of Sciences of the USA, 96, 3143-3148 https://doi.org/10.1073/pnas.96.6.3143
  29. Govoni, G. and Gros, P. (1998). Macrophage NRAMPl and its role in resistance to microbial infections. Inflammatory Research, 47, 277-284 https://doi.org/10.1007/s000110050330
  30. Grotz, N., Fox, T, Connolly, E., Park, W., Guerinot, M.L., and Eide, D. (1998). Identification ofa family of zinc transporter genes from Arabidopsis that respond to zinc deficiency. Proceedings of the National Academy of Sciences of the USA, 95, 7220-7224 https://doi.org/10.1073/pnas.95.12.7220
  31. Gruenheid, S., Canonne-Hergaux, E., Gauthier, S., Hackam, D.J., Gnnstein, and Gros, P. (1999). The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. Journal of Experimental Medicine, 189, 831-841 https://doi.org/10.1084/jem.189.5.831
  32. Gmenheid, S., Cellier, M., Vidal, S., and Gros, P. (1995). Identification and characterization of a second mouse Nramp gene. Genomics, 25, 514-525 https://doi.org/10.1016/0888-7543(95)80053-O
  33. Gunshin, H., Mackeiizie, B., Bereger, U.V, Gunshin, Y., Rometo, M.E, Boron, W.E, Nussberger, S., Gollan, J.L., and Hediger, M.A. (1997). Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature, 338, 482-488
  34. Gutierrez, J. A., Yu, J., and Wessling-Resnick, M. (1998). Characterization and chromosomal mapping of the acuman gene for SFT, a stimulator of Fe transport. Biochemical and Biophysical Research Communications, 253, 739-742 https://doi.org/10.1006/bbrc.1998.9836
  35. Gutierrez, J. A., Yu, J. M., Rivera, S., and Wessling-Resnick, M. (1997). Functional expression cloning aiid characterization of SFT, a stimulator of Fe transport. Journal of Cellular Biology, 139, 895-905 https://doi.org/10.1083/jcb.139.4.895
  36. Han, O., Failla, M.L., Hill, A.D., Morris, E.R., and Smith, J.C.J. (1995). Rcduction of Fe(III). is required for uptake of nonhcmc iron by Caco-2 cells. Journal of Nutrition, 125, 1291-1299
  37. Han, O., FIeet, J.C., and Richard, J.W. (1995). Reciprocal regulation of HFE and Nramp2 gene expression by iron in human intestinal cells. Journal of Nutrition, 129, 98-104
  38. Hanford, J.B. (1994). Cellular iron homcostasis: a paradigm for mechanisms of posttransciiptional control of gcne exprcssion. Progivss in Liver Disease, 12, 47-62
  39. Hirsch, E.C. and Faucheux, B.A. (1998). Iron metabolism and Parkinson's discasc. Movement Disorders, 13, 39-45 https://doi.org/10.1002/mds.870130111
  40. Huang, L. and Gilschier, J. (1997). A novel gene involved in zinc transport is deficient in the lethal milk mouse. NatureGenetics, 17, 292-297
  41. lancu, T.C., Shiloh, H., Raja, K.B., Simpson, R.J., Petters, T.J.,Rerl, D.P, Hsu, A., aiid Good, P.F. (1995). The hypoti-aiis-fenin anemic mouse: ullrastructLiral and laser microprobe analysis observalions. Journul of Puthology, 177, 83-94
  42. Ikeda-Moore, Y., Orimo, H., Hisayasu, S., and Yoshino, Y. (1995). Charactehstics of iron binding to solubillized brush border membrane of the rat intestine. J. Nutr. Sci. Vitaminol, 41,419 https://doi.org/10.3177/jnsv.41.419
  43. Kammler, M., Schon, C., and Hantke, K. (1993). Characterization of the ferrous iron uptake system of Escherichia coli. Jounal of Bacteriology, 175, 6212-219 https://doi.org/10.1128/jb.175.19.6212-6219.1993
  44. Kishi, F. (1994). Isolation aiid Cbaracterization of human Nramp cDNA. Biochem. Biophysic. Res. Commun., 204, 1074-1080 https://doi.org/10.1006/bbrc.1994.2572
  45. Kishi, F. and Tabuchi, M. (1998). Human natual resistance-associated macrophage protein 2: Gene cloning and protein idcntification. Biochem. Biophysic. Res. Commun., 251, 775-783 https://doi.org/10.1006/bbrc.1998.9415
  46. Knopfel, M. Georg, S., Felix, F., and Helmut, H. (2000). Characterization of an integral protein of fhe brush border membrane mediating the transport of divalent metal ions. Biophysical Journal, 79, 874-884 https://doi.org/10.1016/S0006-3495(00)76343-0
  47. Koutnikova, H., Campuzano, V., Fouiy F., Dolle, R, Cazzalini, O., and Doenig, M. (1997). Studies of human, mouse and yeast homologucs indicate an mitochondreal function for frataxin, Nature Genetics, 16, 345-351 https://doi.org/10.1038/ng0897-345
  48. Liu, X.F. aiid Culotta, V.C. (1999). Post-translation control of Nramp metal transport in yeast. Role of meta1 ions and the BSD2 gene. J. Biol. Chem., 274, 4863-4868 https://doi.org/10.1074/jbc.274.8.4863
  49. McMahom. R.J. and Cousins, R.J. (1998). Mammalian zinc transporters. Journal of Nutrition, 128, 667-670
  50. Mercer, J.E, Livingston, J., Hall, B., Paynter, J.A., Begy, C., Chandrasekharappa, S., Lockhart, P., Grimes, A., Bhave, M and Siemieniak, D. (1993). Isolation of a partial candidate gene for Menkes disease by positional cloning. Nature Genetics, 3, 20-25 https://doi.org/10.1038/ng0193-20
  51. Nclson, N. (1999). Mctal ion transportcrs and homeostasis. EMBO J. 18, 4361-4371 https://doi.org/10.1093/emboj/18.16.4361
  52. Orgad, S., Nelson, H., Segal, D., and Nelson, N. (1998). Metal ions suppress tlie abnormal taste behavior of the Drosophila mutant malvolio. J. Exp. Biol., 201, 115-120
  53. Palmiter, R.D., Cole, T.B., aiid Findley, S.D. (1996a). Znt-2, a mammalian protein that confers resistaiice to zinc by facilitaling vesicular seuestration. EMBO Jouranal, 15, 1784-1791
  54. Palmiter, R.D., Cole, T.B., Quaife, C.J., and Findley, S.D. (1996b). ZnT-3, A putative transporter of zinc into xynaptic vesicles. Proceedings of the National Academy of Sciences of the USA, 93, 14934-14939 https://doi.org/10.1073/pnas.93.25.14934
  55. Parkkila, S., Waheed. A., Britton, R.S., Bacon, B.R., Zhou, X.Y., Tomatsu, S., Fleming, R.E., and Sly, W.S. (1997). Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proceedings of the National Academy of Sciences of the USA, 94, 13198-13202 https://doi.org/10.1073/pnas.94.24.13198
  56. Pepphriell, J.E., Edwards, J.A., and Banncrman R.M. (1982). The kinetics of iron uptake by isolatcd intestinal cells from normal mice and micc with sex-linked anemia. Blood, 60, 635-638
  57. Petris, M.J., Mercer, J.E, Culvenor, J.G., Lockhart, P., Gleeson, P.A., and Camakaris, J. (1996). Ligand-reegulated transport of thc Mcnkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of refulated trafcking. EMBO Journal, 15, 6084-6095
  58. Petrukhin, K., Lutsenko, S., Chernov, L., Ross, B.M., Kaplan, J.H., and Gilliam, T.C. (1994). Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase genomic organization, altemative splicing, and structure/function predictions. Human Molecular Genetics, 3, 1647-1656 https://doi.org/10.1093/hmg/3.9.1647
  59. Picard, V, Govoni, G., Jabado, N., and Gros, P. (2000). Nramp 2(DCT1/DMT1). Expressed at the plasma membrane transports iron and other divalent cations into a calcein accessible cytoplasmic pool. J. Biol Chem., 275, 35738-35745 https://doi.org/10.1074/jbc.M005387200
  60. Radisky, D.C., Babcocok, M.C., and Kapkn, J. (1999). The yeast frataxin bomologue mediates mitochondrial iron efflux, Evidence for a mitochondrial iron cycle. Journal of Biological Chemistry, 274, 4497-4499 https://doi.org/10.1074/jbc.274.8.4497
  61. Raja, K,B., Simpson, R..I., and Peters, T.J. (1992). Investigation of a role for reduction if ferric iron uptake by mouse duodenum. Biochimica et Biophysica Acta, 1135, 141-146 https://doi.org/10.1016/0167-4889(92)90129-Y
  62. Rensing, C., Mitra, B., and Rosen, B.P. (1997). The zntA gene of Escherichia uoli cncodes a Zn(II).-trans1ocation P-type ATPase. Proceedings of the National Academy of Sciences of the USA, 94, 14326-14331 https://doi.org/10.1073/pnas.94.26.14326
  63. Rensing, C., Mitra, B., and Rosen, B.P. (1997). The zntA gene of Escherichia uoli cncodes a Zn(II).-trans1ocation P-type ATPase. Proceedings of the National Academy of Sciences of the USA, 94, 14326-14331 https://doi.org/10.1073/pnas.94.26.14326
  64. Richardson, D.R. and Ponka, P. (1997). The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochimica et Biophysica Acfa, 1331, 1-40 https://doi.org/10.1016/S0304-4157(96)00014-7
  65. Roy, C.N., Penny, D.M., Feder, J.N., and Enns, C.A. (1999). The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. Jounal of Biological Chemistry, 274, 9022-9028 https://doi.org/10.1074/jbc.274.13.9022
  66. Stearman, R., Yuan, D.S., Yamaguchi-Iwai, Y., Klausner, R.D., and Cancis, A. (1996). A pemiease-oxidase complex involved in high-affinity iron uptake in yeast. Science, 271, 1552-1557 https://doi.org/10.1126/science.271.5255.1552
  67. Tabuchi, M., Yoshmori, T., Yamaguchi, K. Yoshida, T., and Kishi, F. (2000). Human Nramp2/DMT1, Which mediates iron transport across endosomal mcmbranc, is localized to late endosomes and lysosomes m HEp-2 cells. J. Biol. Chem., 275, 22220-22228 https://doi.org/10.1074/jbc.M001478200
  68. Tallkvist, J., Bowlus, C.L., and Lonnerdal, B. (2001). DMTl gene expression and cadmium absorption in human absorptive enterocytes. Toxicol. Lett., 122, 171-177 https://doi.org/10.1016/S0378-4274(01)00363-0
  69. Taiidy, S., Williams, M., Leggett, A., Lopez-Jimenez, M., Dedes, M., Ramesh, B., Srai, S.K., and Sharp, P. (2000). Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco2 cells. J. Biol. Chem., 275, 1023-1029 https://doi.org/10.1074/jbc.275.2.1023
  70. Tanzi, R. E., Petrukhin, K., Chemov, L., Pellequer, J.L., Wasco, W., Ross, B., Romano, D. M., Parano, E., Pavone, L, and Brzustowicz, L.M. (1993). The Wilson disease gene is a copper transporting ATPase with homology to the Menkes diseasc gene. Nature Genetics, 5, 344-350 https://doi.org/10.1038/ng1293-344
  71. Teichmannn, R. and Stremmel, W. (1990). lron uptake by human upper small intestinc microvillous membrane vesicles. Indication for a facilitated transport mechanism mediated by a membrane iron-binding protcin. Jounal of Clinical Investigation, 86, 2145-2153 https://doi.org/10.1172/JCI114953
  72. Umbreit, J.N., Conrad, M.E., Moore, E.G., Dcsai, M.R, aiid Turrens, J. (1996). Paraferritin: a Protein complex with ferrireductasc activity is associated with iron absorption in rats. Biochemistry, 35, 6460-6469 https://doi.org/10.1021/bi951927s
  73. Van Eijk, H.G. and De Jong, G. (1992). The physiology of iron, transferrin, and ferritin. Biological Trace. Element Research, 35, 13-24
  74. Vidal, S., Belouchi, A.M., Cellier, M., Beatty, B., and Gros, P. (1995a). Cloning and characterizatioii of a second human Nramp gene on chromosome 12q13. Mammalian Genome, 6, 224-230 https://doi.org/10.1007/BF00352405
  75. Vidal, S., Gros, R., and Skamene, E. (1995b). Natural resistance to infection with intracellular parasites: Molecular genetics identifies Nrampl as the Bcg/Ity/Lsh locus. Journal of Leukocyte Biology, 58, 382-390
  76. Vidal, S., M., Malo, D., Vogan, K., Skamene, E., and Gros, P. (1993). Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell, 73, 469-485 https://doi.org/10.1016/0092-8674(93)90135-D
  77. Vulpe, C., Levmson, B., Whitney, S., Packman, S., and Gitschiter, J. (1993). Isolation of a candidate gene of Menkes disease and evidence that it encodes a copper-transporting ATPase. Nature Genetics, 3, 7-13 https://doi.org/10.1038/ng0193-7
  78. Wessling-Resnick, M. (2000). Iron transport. Annu. Rev. Nutr., 20, 129-151 https://doi.org/10.1146/annurev.nutr.20.1.129
  79. Wien, E.M. and Van Campen, D.R. (1991). Ferric iron absoiption in rats: relationship to iron status, endogenous sulfhydiyl and other redox components in the intestinal lumen. Journal of Nutrition, 121, 825-831
  80. Williams, S.R. (1993). Minerals. In Nuthtion and Diet Thempy. pp. 220-268. Mosby-Year Book, St. Louis
  81. Wilson, R.B. and Roof, D.M. (1997). Respiralory deficiency due to loss of mitochondrial DNA in yeast lacking the trataxin homologue. Nature Genetics, 16, 352-357 https://doi.org/10.1038/ng0897-352
  82. Wood, R.J. and Han, O. (1998). Recent advanccs in nutritional science; Recently identified molecular aspects of intestinal iron absorption. J. Nutr., 128, 1841-1844
  83. Zhao, H. and Eide, D. (1996a). The yeast ZRTl gene encodcs the zinc transporter protein of a high-affinity uptake system induced by zinc limitation. Proceedings of the National Academy of Sciences of the USA, 93, 2454-2458 https://doi.org/10.1073/pnas.93.6.2454
  84. Zhao, H. and Eidc, D. (1996b). The ZRT2 gene encodes the low affmity zinc transporter in Saccharomyces cerevisiae. Journal of Biological Chemistry, 271, 23203-23210 https://doi.org/10.1074/jbc.271.38.23203
  85. Zhou, B. and Gitschier, J. (1997). hCTRl-A human gene for copper uptake identified by complementation in yeast. Proceedings of the National Academy of Sciences of the USA, 94, 7481-7486 https://doi.org/10.1073/pnas.94.14.7481
  86. Zwillmg, B.S., Kuhn, D.E., Wikoff; D.B., and Lafusc, W. (1999). Role of iron in Nramp 1-mediated inhibition of mycobacterial growth. Infection & Immunity, 67, 1386-1392