The Interaction of Nonheme Iron with Immature Red Cells

  • Anatoly Bezkorovainy
Part of the Biochemistry of the Elements book series (BOTE, volume 1)


It was seen in Chapter 2 that circulating iron can find its way into the bone marrow cells, liver cells, and cells of other organs. Iron, in turn, can enter the circulation from the reticuloendothelial system, parenchymal storage sites, mucosal cells, and a variety of other systems. All such processes involve cell membrane transport mechanisms, and most involve serotransferrin and ferritin as well, either directly or indirectly. In this chapter we shall be concerned with the mechanisms whereby nonheme iron can find its way into the immature red cells and the pertinent intracellular iron metabolic pathways.


Iron Uptake Transferrin Receptor Nonheme Iron Sideroblastic Anemia Isonicotinic Acid Hydrazide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aisen, P., and Leibman, A., 1968. Citrate-mediated exchange of Fe3+ among transferrin molecules, Biochem. Biophys. Res. Commun. 32: 220–226.CrossRefGoogle Scholar
  2. Aisen, P., and Leibman, A., 1973. The role of the anion-binding site of transferrin in its interaction with the reticulocyte, Biochim. Biophys. Acta 304: 797–804.PubMedCrossRefGoogle Scholar
  3. Aisen, P., Leibman, A., Pinkowitz, R. A., and Pollack, S., 1973. Exchangeability of bicarbonate specifically bound to transferrin, Biochemistry 12: 3679–3684.PubMedCrossRefGoogle Scholar
  4. Awai, M., Chipman, B., and Brown, E. B., 1975a. In vivo evidence for the functional heterogeneity of transferrin-bound iron. I. Studies in normal rats, J. Lab. Clin. Med. 85: 769–784.PubMedGoogle Scholar
  5. Awai, M., Chipman, B., and Brown, E. B., 1975b. In vivo evidence for the functional heterogeneity of transferrin-bound iron. II. Studies in pregnant rats, J. Lab. Clin. Med. 85: 785–796.PubMedGoogle Scholar
  6. Baker, E., and Morgan, E. H., 1969. The kinetics of the interaction between rabbit transferrin and reticulocytes, Biochemistry 8: 1133–1141.PubMedCrossRefGoogle Scholar
  7. Bezkorovainy, A., 1966. Comparative study of metal-free, iron-saturated, and sialic acid-free transferrins, Biochim. Biophys. Acta 127: 535–537.PubMedCrossRefGoogle Scholar
  8. Black, C., Glass, J., Nunez, M. T., and Robinson, S. H., 1979. Transferrin binding and iron transport in iron-deficient and iron replete rat reticulocytes, J. Lab. Clin. Med. 93: 645–651.PubMedGoogle Scholar
  9. Borochov, H., and Shinitzky, M., 1976. Vertical displacement of membrane proteins mediated by changes in microviscosity, Proc. Natl. Acad. Sci. U.S.A. 73: 4526–4530.PubMedCrossRefGoogle Scholar
  10. Borova, J., Ponka, P., and Neuwirt, J., 1973. Study of intracellular iron distribution in rabbit reticulocytes with normal and inhibited heme synthesis, Biochim. Biophys. Acta 320: 143–156.PubMedCrossRefGoogle Scholar
  11. Brock, J. H., and Esparza, I., 1979. Failure of reticulocytes to take up iron from lactoferrin saturated by various methods, Br. J. Haematol. 42: 481–483.PubMedCrossRefGoogle Scholar
  12. Brown, E. B., Okada, S., Awai, M., and Chipman, B., 1975. In vivo evidence for the functional heterogeneity of transferrin-bound iron. III. Studies of transferrin at high and low iron saturation, J. Lab. Clin. Med., 85: 576–585.Google Scholar
  13. Carver, F. J., and Frieden, E., 1978. Factors affecting the adenosine triphosphate induced release of iron from transferrin. Biochemistry 17: 167–172.PubMedCrossRefGoogle Scholar
  14. Christensen, A. C., Huebers, H., and Finch, C., 1978. Effect of transferrin saturation on iron delivery in rats, Am. J. Physiol. 235: R18–R22.PubMedGoogle Scholar
  15. Edwards, S. A., and Fielding, J., 1971. Studies of the effect of sulfhydryl and other inhibitors on reticulocyte uptake of doubly-labelled transferrin, Br. J. Haematol. 20: 405–416.PubMedCrossRefGoogle Scholar
  16. Egyed, A., 1973. The significance of transferrin–bound bicarbonate in the uptake of iron by reticulocytes, Biochim. Biophys. Acta 304: 805–813.PubMedCrossRefGoogle Scholar
  17. Eldor, A., Manny, N., and Izak, G., 1970. The effect of transferrin-free serum on the utilization of iron by rabbit reticulocytes, Blood 36: 233–238.PubMedGoogle Scholar
  18. Faulk, W. P., and Galbraith, G. M. P., 1979. Trophoblast transferrin and transferrin receptors in the host–parasite relationship in human pregnancy, Proc. R. Soc. London Ser. B 204: 83–97.CrossRefGoogle Scholar
  19. Fielding, J., and Speyer, B. E., 1974. Iron transport intermediates in human reticulocytes and membrane binding site of iron-transferrin, Biochim. Biophys. Acta 363: 387–396.PubMedCrossRefGoogle Scholar
  20. Fletcher, J., 1969. Variation in the availability of transferrin-bound iron for uptake by immature red cells, Clin. Sci. 37: 273–297.PubMedGoogle Scholar
  21. Fletcher, J., and Huehns, E. R., 1967. Significance of the binding of iron by transferrin, Nature (London) 215: 584–586.CrossRefGoogle Scholar
  22. Fletcher, J., and Huehns, E. R., 1968. Function of transferrin, Nature (London) 218: 1211–1214.CrossRefGoogle Scholar
  23. Garrett, N. E., Garrett, R. J. B., and Archdeacon, J. W., 1973. Solubilization and chromatography of iron-binding compounds from reticulocyte stroma, Biochem. Biophys. Res. Commun. 52: 466–474.PubMedCrossRefGoogle Scholar
  24. Garrick, L. M., Edwards, J. A., and Hoke, J. E., 1978. The effect of hemin on globin synthesis and iron uptake by reticulocytes of the Belgrade rat, FEBS Lett. 93: 109–114.PubMedCrossRefGoogle Scholar
  25. Hahn, D., 1973. Functional behaviour of transferrin, Eur. J. Biochem. 34: 311–316.CrossRefGoogle Scholar
  26. Hahn, D., Baviera, B., and Ganzoni, A. M., 1975. Functional heterogeneity of the transport iron compartment, Acta Haematol. 53: 285–291.PubMedCrossRefGoogle Scholar
  27. Harris, D. C., 1977. Functional equivalence of iron bound to human transferrin at low pH or high pH, Biochim. Biophys. Acta 496: 563–565.PubMedCrossRefGoogle Scholar
  28. Harris, D. C., and Aisen, P., 1975a. Functional equivalence of the two iron–binding sites of human transferrin, Nature (London) 257: 821–823.CrossRefGoogle Scholar
  29. Harris, D. C., and Aisen, P., 1975b. Iron-donating properties of transferrin, Biochemistry 14: 262–268.PubMedCrossRefGoogle Scholar
  30. Hemmaplardh, D., and Morgan, E. H., 1977. The role of endocytosis in transferrin uptake by reticulocyte and bone marrow cells, Br. J. Haematol. 36: 85–96.PubMedCrossRefGoogle Scholar
  31. Hemmaplardh, D., Kailis, S. G., and Morgan, E. H., 1974. The effects of inhibitors of microtubule and microfilament function on transferrin and iron uptake by rabbit reticulocytes and bone marrow, Br. J. Haematol. 28: 53–65.PubMedCrossRefGoogle Scholar
  32. Hu, H.-Y. Y., and Aisen, P., 1978. Molecular characteristics of the transferrin-receptor complex of the rabbit reticulocyte, J. Supramol. Struct. 8: 349–360.PubMedCrossRefGoogle Scholar
  33. Huebers, H., Huebers, E., Csiba, E., and Finch, C. A., 1978. Iron uptake from rat plasma transferrin by rat reticulocytes, J. Clin. Invest. 62: 944–951.PubMedCrossRefGoogle Scholar
  34. Jandl, J. H., and Katz, J. H., 1963. The plasma-to-cell cycle of transferrin, J. Clin. Invest. 42: 314–326.PubMedCrossRefGoogle Scholar
  35. Jandl, J. H., Inman, J. H., Simmons, R. L., and Allen, D. W., 1959. Transfer of iron from serum iron-binding protein to human reticulocytes, J. Clin. Invest. 38: 161–185.PubMedCrossRefGoogle Scholar
  36. Kailis, S. G., and Morgan, E. H., 1974. Transferrin and iron uptake by rabbit bone marrow cells in vitro, Br. J. Haematol. 28: 37–52.PubMedCrossRefGoogle Scholar
  37. Karibian, D., and London, I. M., 1965. Control of heme synthesis by feedback inhibition, Biochem. Biophys. Res. Commun. 18: 243–249.PubMedCrossRefGoogle Scholar
  38. Katz, J. H., 1965. The delivery of iron into the immature red cell: A critical review, Ser. Haematol. 6: 15–29.Google Scholar
  39. Konopka, L., and Hoffbrand, A. V., 1979. Haem synthesis in sideroblastic anemia, Br. J. Haematol. 42: 73–83.PubMedCrossRefGoogle Scholar
  40. Konopka, K., and Szotor, M., 1972. Determination of iron in the acid–soluble fraction of human erythrocytes, Acta Haematol. 47: 157–163.PubMedCrossRefGoogle Scholar
  41. Kornfeld, S., 1968. The effects of structural modifications on the biologic activity of human transferrin, Biochemistry 7: 945–954.PubMedCrossRefGoogle Scholar
  42. Kornfeld, S., 1969. The effect of metal attachment to human apotransferrin on its binding to reticulocytes, Biochim. Biophys. Acta 194: 25–33.PubMedGoogle Scholar
  43. Lane, R. S., 1971. Binding of transferrin and metal ions by suspensions of reticulocyterich rabbit blood, Biochim. Biophys. Acta 243: 193–197.PubMedGoogle Scholar
  44. Lane, R. S., 1972. Transferrin-reticulocyte binding: Evidence for the functional importance of transferrin conformation, Br. J. Haematol. 22: 309–317.PubMedCrossRefGoogle Scholar
  45. Larrick, J. W., and Cresswell, P., 1979. Transferrin receptors on human B and T lymphoblastoid cell lines, Biochim. Biophys. Acta 583: 483–490.PubMedCrossRefGoogle Scholar
  46. Leibman, A., and Aisen, P., 1977. Transferrin receptor of the rabbit reticulocyte, Biochemistry 16: 1268–1272.PubMedCrossRefGoogle Scholar
  47. Light, N. D., 1977. The isolation and partial characterization of transferrin binding components of the rabbit reticulocyte plasma membrane, Biochim. Biophys. Acta 495: 46–57.PubMedGoogle Scholar
  48. Light, N. D., 1978. Further studies on the rabbit erythroid cell plasma membrane transferrin receptor, Biochem. Biophys. Res. Commun. 81: 261–267.PubMedCrossRefGoogle Scholar
  49. Loh, T. T., Yeung, Y. G., and Yeung, D., 1977. Transferrin and iron uptake by rabbit reticulocytes, Biochim. Biophys. Acta 471: 118–124.PubMedCrossRefGoogle Scholar
  50. Martinez-Medellin, J., and Benavides, L., 1979. The rate-limiting step in the reticulocyte uptake of transferrin and transferrin iron, Biochim. Biophys. Acta 584: 84–93.PubMedCrossRefGoogle Scholar
  51. Martinez-Medellin, J., and Schulman, H. M., 1972. The kinetics of iron and transferrin incorporation into rabbit erythroid cells and the nature of stromal-bound iron, Biochim. Biophys. Acta 264: 272–284.PubMedCrossRefGoogle Scholar
  52. Martinez-Medellin, J., Schulman, H. M., DeMiguel, E., and Benavides, L., 1977. New evidence for the internalization of functional transferrin in rabbit reticulocytes, in Proteins of Iron Metabolism, E. B. Brown, P. Aisen, J. Fielding, and R. R. Crichton (eds.), Grune and Stratton, New York, pp. 305–310.Google Scholar
  53. Morgan, E. H., 1964. The interaction between rabbit, human, and rat transferrin and reticulocytes, Br. J. Haematol. 10: 442–452.PubMedCrossRefGoogle Scholar
  54. Morgan, E. H., 1971. A study of iron transfer from rabbit transferrin to reticulocytes using synthetic chelating agents, Biochim. Biophys. Acta 244: 103–116.PubMedCrossRefGoogle Scholar
  55. Morgan, E. H., 1976. Failure of a cell-free system from rabbit reticulocytes to remove iron from transferrin, Biochem. J. 158: 489–491.PubMedGoogle Scholar
  56. Morgan, E. H., 1977. Iron exchange between transferrin molecules mediated by phosphate compounds and other cell metabolites, Biochim. Biophys. Acta 499: 169–177.PubMedCrossRefGoogle Scholar
  57. Morgan, E. H., and Appleton, T. C., 1969. Autoradiographic localization of 125I labelled transferrin in rabbit reticulocytes, Nature (London) 223: 1371–1372.CrossRefGoogle Scholar
  58. Morgan, E. H., and Baker, E., 1969. The effect of metabolic inhibitors on transferrin and iron uptake and transferrin release from reticulocytes, Biochim. Biophys. Acta 184: 442–454.PubMedCrossRefGoogle Scholar
  59. Morgan, E. H., Huebers, H., and Finch, C. A., 1978. Differences between the binding sites for iron binding and release in human and rat transferrin, Blood 52: 1219–1228.PubMedGoogle Scholar
  60. Muller, C., and Shinitzky, M., 1979. Modulation of transferrin receptors in bone marrow cells by changes in lipid fluidity, Br. J. Haematol. 42: 355–362.PubMedCrossRefGoogle Scholar
  61. Neuwirt, J., Borova, J., and Ponka, P., 1975. Intracellular iron kinetics in erythroid cells, in Proteins of Iron Storage and Transport in Biochemistry and Medicine, R. R. Crichton (ed.), North-Holland, Amsterdam, pp. 161–166.Google Scholar
  62. Nunez, M., Fischer, S., Glass, J., and Lavidor, L., 1977. The crosslinking of 125I-labelled transferrin to rabbit reticulocytes, Biochim. Biophys. Acta 490: 87–93.PubMedGoogle Scholar
  63. Nunez, M. T., Glass, J., and Robinson, S. H., 1978. Mobilization of iron from the plasma membrane of the murine reticulocytes. The role of ferritin, Biochim. Biophys. Acta 509: 170–180.PubMedCrossRefGoogle Scholar
  64. Okada, S., Chipman, B., and Brown, E. B., 1977. In vivo evidence for the functional heterogeneity of transferrin-bound iron. IV. Selective uptake by erythroid precursors of radioiron from portal vein plasma transferrin during intestinal iron absorption, J. Lab. Clin. Med. 89: 51–64.PubMedGoogle Scholar
  65. Okada, S., Rossmann, M. D., and Brown, E. B., 1978. The effect of acid pH and citrate on the release and exchange of iron on rat transferrin, Biochim. Biophys. Acta 543: 72–81.PubMedCrossRefGoogle Scholar
  66. Okada, S., Jarvis, B., and Brown, E. B., 1979. In vivo evidence for the functional heterogeneity of transferrin-bound iron. V. Isotransferrin: An explanation of the Fletcher-Huehns phenomenon in the rat, J. Lab. Clin. Med. 93: 189–198.PubMedGoogle Scholar
  67. Ponka, P., and Neuwirt, J., 1972. The effect of plasma and transferrin on the hemin inhibition of iron uptake by reticulocytes, Experientia 28: 189–190.PubMedCrossRefGoogle Scholar
  68. Ponka, P., and Neuwirt, J., 1974. Annotation: Haem synthesis and iron uptake by reticulocytes, Br. J. Haematol. 28: 1–5.PubMedCrossRefGoogle Scholar
  69. Ponka, P., Neuwirt, J., and Borova, J., 1974. The role of heme in the release of iron from transferrin in reticulocytes, Enzyme 17: 91–99.PubMedGoogle Scholar
  70. Ponka, P., Neuwirt, J., Borova, J., and Fuchs, O., 1977. The role of mitochondria in the control of iron delivery to hemoglobin molecules, in Proteins of Iron Metabolism, E. B. Brown, P. Aisen, J. Fielding, and R. R. Crichton (eds.), Grune and Stratton, New York, pp. 319–326.Google Scholar
  71. Ponka, P., Borova, J., Neuwirt, J., and Fuchs, O., 1979a. Mobilization of iron from reticulocytes, FEBS Lett. 97: 317–321.PubMedCrossRefGoogle Scholar
  72. Ponka, P., Borova, J., Neuwirt, J., Fuchs, O., and Necas, E., 1979b. A study of intracellular iron metabolism using pyridoxal isonicotinyl hydrazone and other synthetic chelating agents, Biochim. Biophys. Acta 586: 278–297.PubMedCrossRefGoogle Scholar
  73. Schulman, H. M., Martinez-Medellin, J., and Sidloi, R., 1974. The reticulocyte-mediated release of iron and bicarbonate from transferrin: Effect of metabolic inhibitors, Biochim. Biophys. Acta 343: 529–534.PubMedCrossRefGoogle Scholar
  74. Skarberg, K., Eng, M., Huebers, H., Marsaglia, G., and Finch, C., 1978. Plasma radioiron kinetics in man: Explanation for the effect of plasma iron concentration, Proc. Natl. Acad. Sci. U.S.A. 75: 1559–1561.PubMedCrossRefGoogle Scholar
  75. Sly, D. A., Grohlich, D., and Bezkorovainy, A., 1975a. Transferrin receptors from reticulocyte membranes and cytosol, in Proteins of Iron Storage and Transport in Biochemistry and Medicine, R. R. Crichton (ed.), North-Holland, Amsterdam, pp. 141–145.Google Scholar
  76. Sly, D. A., Grohlich, D., and Bezkorovainy, A., 1975b. Transferrin in the reticulocyte cytosol, Biochim. Biophys. Acta 385: 36–40.PubMedCrossRefGoogle Scholar
  77. Sly, D. A., Grohlich, D., and Bezkorovainy, A., 1978. Transferrin receptor from rabbit reticulocyte membranes, in Cell Surface Carbohydrate Chemistry, R. E. Harmon (ed.), Academic Press, New York, pp. 255–268.Google Scholar
  78. Speyer, B. E. and Fielding, J., 1974. Chromatographic fractionation of human reticulocytes after uptake of doubly labelled (59Fe, 125I) transferrin, Biochim. Biophys. Acta 332: 192–200.CrossRefGoogle Scholar
  79. Speyer, B. E., and Fielding, J., 1979. Ferritin as a cytosol iron transport intermediate in human reticulocytes, Br. J. Haematol. 42: 255–267.PubMedCrossRefGoogle Scholar
  80. Sullivan, A. L., and Weintraub, L. R., 1978. Identification of 125I-labeled rat reticulocyte membrane proteins with affinity for transferrin, Blood 52: 436–446.PubMedGoogle Scholar
  81. Sullivan, A. L., Grasso, J. A., and Weintraub, L. R., 1976. Micropinocytosis of transferrin by developing red cells: An electron microscopic study utilizing ferritin-conjugated transferrin and ferritin-conjugated antibodies to transferrin, Blood 47: 133–143.PubMedGoogle Scholar
  82. Ulvik, R., and Romslo, I., 1978. Studies on the utilization of ferritin iron in the ferrochelatase reaction of isolated rat liver mitochondria, Biochim. Biophys. Acta 541: 251–262.PubMedCrossRefGoogle Scholar
  83. Van Bockxmeer, F. M., and Morgan, E. H., 1977. Identification of transferrin receptors in reticulocytes, Biochim. Biophys. Acta 468: 437–450.PubMedCrossRefGoogle Scholar
  84. Van Bockxmeer, F., Hemmaplardh, D., and Morgan, E. H., 1975. Studies on the binding of transferrin to cell membrane receptors, in Proteins of Iron Storage and Transport in Biochemistry and Medicine, R. R. Crichton (ed.), North-Holland, Amsterdam, pp. 111–119.Google Scholar
  85. Van Bockxmeer, F. M., Yates, G. K., and Morgan, E. H., 1978. Interaction of transferrin with solubilized receptors from reticulocytes, Eur. J. Biochem. 92: 147–154.PubMedCrossRefGoogle Scholar
  86. VanderHeul, C., Kroos, M. J., and Van Eijk, H. G., 1978. Binding sites of iron transferrin on rat reticulocytes. Inhibition by specific antibodies, Biochim. Biophys. Acta 511: 430–441.PubMedCrossRefGoogle Scholar
  87. Verhoef, N. J., and Noordeloos, P. J., 1977. Binding of transferrin and uptake of iron by rat erythroid cells in vitro, Clin. Sci. Mol. Med. 52: 87–96.PubMedGoogle Scholar
  88. Verhoef, N. J., Kottenhagen, M. J., Mulder, H. J. M., Noordeloos, P. J., and Leijnse, B., 1978. Functional heterogeneity of transferrin-bound iron, Acta Haematol. 60: 210–226.PubMedCrossRefGoogle Scholar
  89. Walsh, R. J., Thomas, E. D., Chow, S. K., Fluharty, R. G., and Finch, C. A., 1949. Iron metabolism. Heme synthesis in vitro by immature erythrocytes, Science 110: 396–398.PubMedCrossRefGoogle Scholar
  90. Williams, S. C., and Woodworth, R. C., 1973. The interaction of iron-conalbumin (anion) complexes with chick embryo red blood cells, J. Biol. Chem. 248: 5848–5853.PubMedGoogle Scholar
  91. Witt, D. P., and Woodworth, R. C., 1975. Interaction of affinity labeled conalbumin with reticulocyte membranes, in Proteins of Iron Storage and Transport in Biochemistry and Medicine, R. R. Crichton (ed.), North-Holland, Amsterdam, pp. 133–140.Google Scholar
  92. Witt, D. P., and Woodworth, R. C., 1978. Identification of the transferrin receptor of the rabbit reticulocyte, Biochemistry 17: 3913–3917.PubMedCrossRefGoogle Scholar
  93. Workman, E. F., and Bates, G. W., 1974. Mobilization of iron from reticulocyte ghosts by cytoplasmic agents, Biochem. Biophys. Res. Commun. 58: 787–794.PubMedCrossRefGoogle Scholar
  94. Zapolski, E. J., and Princiotto, J. V., 1976. Failure of rabbit reticulocytes to incorporate conalbumin or lactoferrin iron, Biochim. Biophys. Acta 421: 80–86.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1980

Authors and Affiliations

  • Anatoly Bezkorovainy
    • 1
  1. 1.Rush-Presbyterian-St. Luke’s Medical CenterChicagoUSA

Personalised recommendations