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Structure and function of normal hemoglobins

Martin H Steinberg, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Jennifer S Tirnauer, MD


The structure and function of the normal human hemoglobins (ie, adult hemoglobin [hemoglobin A, HbA], hemoglobin A2 [HbA2], fetal hemoglobin [HbF], and the embryonic hemoglobins) will be discussed here, although fetal hemoglobin is discussed in greater detail separately. (See "Fetal hemoglobin (hemoglobin F) in health and disease".)

Abnormal hemoglobins are discussed separately. (See "Genetic disorders of hemoglobin oxygen affinity" and "Introduction to hemoglobin mutations" and "Unstable hemoglobin variants" and "Sickle hemoglobin polymer: Structure and functional properties".)


The study of hemoglobins, both normal and mutant, has provided fundamental insight into structure-function relationships of proteins in general and, in particular, the molecular basis of oxygen transport. The discovery that sickle hemoglobin has an abnormal electrophoretic mobility began the era of molecular medicine [1]. With the advent of recombinant DNA technology, research on hemoglobin provided early and important information about the organization and regulation of genes as well as insights as to how ontogeny affects gene expression [2].

Proteins with hemoglobin-like function (ie, hemoglobin motifs) can be found in the most ancient unicellular plants and animals and have evolved over hundreds of millions of years into gas transport proteins through the processes of gene duplication, conversion, divergence, and inactivating mutations [3]. In man, these processes have culminated in hemoglobin gene clusters on separate chromosomes (figure 1), whose expression is developmentally regulated [4]. (See 'Structure' below.)

All human hemoglobin genes contain three exons separated by two introns; the exons may encode distinct functional domains of the molecule. The tetrameric globular structure of hemoglobin is adapted to the physiology of complex organisms and their needs for regulation of oxygen delivery far better than the primitive globins hemocyanin or erythrocruorin, and single chain globins such as muscle myoglobin, cytoglobin, and neuroglobin.

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Literature review current through: Sep 2017. | This topic last updated: Sep 28, 2016.
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  1. PAULING L, ITANO HA. Sickle cell anemia a molecular disease. Science 1949; 110:543.
  2. Schechter AN. Hemoglobin research and the origins of molecular medicine. Blood 2008; 112:3927.
  3. Hardison RC. Evolution of hemoglobin and its genes. Cold Spring Harb Perspect Med 2012; 2:a011627.
  4. Hardison R. Hemoglobins from bacteria to man: evolution of different patterns of gene expression. J Exp Biol 1998; 201:1099.
  5. Perutz MF. Molecular anatomy, physiology, and pathology of hemoglobin. In: The Molecular Basis of Blood Disorders, Stamatoyannopoulos G, Nienhuis AW, et al. (Eds), WB Saunders, Philadelphia 1987. p.127.
  7. Bohr C, Hasselbalch K, Krogh A. Ueber einen in biologischer Beziehung wichtigen Einfluss. den die Kohlen- sauerespannung des Blutes auf dessen Sauerstoffbinding ubt. Skand Arch Physiol 1904; 16:402.
  8. Riggs AF. The Bohr effect. Annu Rev Physiol 1988; 50:181.
  9. Busch MR, Mace JE, Ho NT, Ho C. Roles of the beta 146 histidyl residue in the molecular basis of the Bohr effect of hemoglobin: a proton nuclear magnetic resonance study. Biochemistry 1991; 30:1865.
  10. Bunn HF, Forget BG. Hemoglobin: Molecular, Genetic and Clinical Aspects, WB Saunders, Philadelphia 1986.
  11. Lemarchandel V, Joulin V, Valentin C, et al. Compound heterozygosity in a complete erythrocyte bisphosphoglycerate mutase deficiency. Blood 1992; 80:2643.
  12. Petousi N, Copley RR, Lappin TR, et al. Erythrocytosis associated with a novel missense mutation in the BPGM gene. Haematologica 2014; 99:e201.
  13. Rosa R, Prehu MO, Beuzard Y, Rosa J. The first case of a complete deficiency of diphosphoglycerate mutase in human erythrocytes. J Clin Invest 1978; 62:907.
  14. Pawloski JR, Stamler JS. Nitric oxide in RBCs. Transfusion 2002; 42:1603.
  15. Jia L, Bonaventura C, Bonaventura J, Stamler JS. S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control. Nature 1996; 380:221.
  16. Stamler JS, Jia L, Eu JP, et al. Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science 1997; 276:2034.
  17. Gow AJ, Stamler JS. Reactions between nitric oxide and haemoglobin under physiological conditions. Nature 1998; 391:169.
  18. Crawford JH, Isbell TS, Huang Z, et al. Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. Blood 2006; 107:566.
  19. Gladwin MT, Kim-Shapiro DB. The functional nitrite reductase activity of the heme-globins. Blood 2008; 112:2636.
  20. Hofmann O, Mould R, Brittain T. Allosteric modulation of oxygen binding to the three human embryonic haemoglobins. Biochem J 1995; 306 ( Pt 2):367.
  21. Hofmann OM, Brittain T. Partitioning of oxygen and carbon monoxide in the three human embryonic hemoglobins. Hemoglobin 1998; 22:313.
  22. Sutherland-Smith AJ, Baker HM, Hofmann OM, et al. Crystal structure of a human embryonic haemoglobin: the carbonmonoxy form of gower II (alpha2 epsilon2) haemoglobin at 2.9 A resolution. J Mol Biol 1998; 280:475.
  23. Zheng T, Zhu Q, Brittain T. Origin of the suppression of chloride ion sensitivity in human embryonic hemoglobin Gower II. IUBMB Life 1999; 48:435.
  24. Zheng T, Brittain T, Watmough NJ, Weber RE. The role of amino acid alpha38 in the control of oxygen binding to human adult and embryonic haemoglobin Portland. Biochem J 1999; 343 Pt 3:681.
  25. Thein SL, Menzel S, Lathrop M, Garner C. Control of fetal hemoglobin: new insights emerging from genomics and clinical implications. Hum Mol Genet 2009; 18:R216.
  26. Alter BP, Rosenberg PS, Day T, et al. Genetic regulation of fetal haemoglobin in inherited bone marrow failure syndromes. Br J Haematol 2013; 162:542.
  27. Sankaran VG, Menne TF, Xu J, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 2008; 322:1839.
  28. Sankaran VG, Xu J, Orkin SH. Advances in the understanding of haemoglobin switching. Br J Haematol 2010; 149:181.
  29. Masuda T, Wang X, Maeda M, et al. Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science 2016; 351:285.
  30. Zhou D, Liu K, Sun CW, et al. KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genet 2010; 42:742.
  31. Sankaran VG, Nathan DG. Reversing the hemoglobin switch. N Engl J Med 2010; 363:2258.
  32. Wilber A, Nienhuis AW, Persons DA. Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. Blood 2011; 117:3945.
  33. Tallack MR, Perkins AC. Three fingers on the switch: Krüppel-like factor 1 regulation of γ-globin to β-globin gene switching. Curr Opin Hematol 2013; 20:193.
  34. Amaya M, Desai M, Gnanapragasam MN, et al. Mi2β-mediated silencing of the fetal γ-globin gene in adult erythroid cells. Blood 2013; 121:3493.
  35. Bauer DE, Kamran SC, Lessard S, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 2013; 342:253.
  36. Borg J, Papadopoulos P, Georgitsi M, et al. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet 2010; 42:801.
  37. Sankaran VG, Xu J, Byron R, et al. A functional element necessary for fetal hemoglobin silencing. N Engl J Med 2011; 365:807.
  38. Forget BG. Progress in understanding the hemoglobin switch. N Engl J Med 2011; 365:852.
  39. Ghedira ES, Lecerf L, Faubert E, et al. Estimation of the difference in HbF expression due to loss of the 5' δ-globin BCL11A binding region. Haematologica 2013; 98:305.
  40. Huisman TH, Schroeder WA, Bannister WH, Grech JL. Evidence for four nonallelic structural genes for the chain of human fetal hemoglobin. Biochem Genet 1972; 7:131.
  41. Miwa I, Erdös EG, Seki T. Presence of three peptides in urinary kinin (substance Z) preparations. Life Sci 1968; 7:1339.
  42. Tyuma I, Shimizu K. Different response to organic phosphates of human fetal and adult hemoglobins. Arch Biochem Biophys 1969; 129:404.
  43. Adachi K, Konitzer P, Pang J, et al. Amino acids responsible for decreased 2,3-biphosphoglycerate binding to fetal hemoglobin. Blood 1997; 90:2916.
  44. Nagel RL, Steinberg MH. of the embryo and fetus and minor hemoglobins of adults. In: Disorders of Hemoglobin: Genetics, pathophysiology, clinical management, Steinberg MH, Forget BG, Higgs DR, et al. (Eds), Cambridge University Press, Cambridge 2001.
  45. Boyer SH, Belding TK, Margolet L, Noyes AN. Fetal hemoglobin restriction to a few erythrocytes (F cells) in normal human adults. Science 1975; 188:361.
  46. Wood WG, Stamatoyannopoulos G, Lim G, Nute PE. F-cells in the adult: normal values and levels in individuals with hereditary and acquired elevations of Hb F. Blood 1975; 46:671.
  47. Forget BG. Molecular basis of hereditary persistence of fetal hemoglobin. Ann N Y Acad Sci 1998; 850:38.
  48. Craig JE, Rochette J, Sampietro M, et al. Genetic heterogeneity in heterocellular hereditary persistence of fetal hemoglobin. Blood 1997; 90:428.
  49. Craig JE, Rochette J, Fisher CA, et al. Dissecting the loci controlling fetal haemoglobin production on chromosomes 11p and 6q by the regressive approach. Nat Genet 1996; 12:58.
  50. Amato A, Cappabianca MP, Perri M, et al. Interpreting elevated fetal hemoglobin in pathology and health at the basic laboratory level: new and known γ- gene mutations associated with hereditary persistence of fetal hemoglobin. Int J Lab Hematol 2014; 36:13.
  51. Martin SL, Vincent KA, Wilson AC. Rise and fall of the delta globin gene. J Mol Biol 1983; 164:513.
  52. Steinberg MH, Adams JG 3rd. Hemoglobin A2: origin, evolution, and aftermath. Blood 1991; 78:2165.
  53. Tang DC, Rodgers GP. Activation of the human delta-globin gene promoter in primary adult erythroid cells. Br J Haematol 1998; 103:835.
  54. Manchinu MF, Marongiu MF, Poddie D, et al. In vivo activation of the human δ-globin gene: the therapeutic potential in β-thalassemic mice. Haematologica 2014; 99:76.
  55. Steinberg MH, Rodgers GP. HbA2 : biology, clinical relevance and a possible target for ameliorating sickle cell disease. Br J Haematol 2015; 170:781.
  56. Menzel S, Garner C, Rooks H, et al. HbA2 levels in normal adults are influenced by two distinct genetic mechanisms. Br J Haematol 2013; 160:101.
  57. Griffin PJ, Sebastiani P, Edward H, et al. The genetics of hemoglobin A2 regulation in sickle cell anemia. Am J Hematol 2014; 89:1019.
  59. Roberts AV, Weatherall DJ, Clegg JB. The synthesis of human haemoglobin A 2 during erythroid maturation. Biochem Biophys Res Commun 1972; 47:81.
  60. Perseu L, Satta S, Moi P, et al. KLF1 gene mutations cause borderline HbA(2). Blood 2011; 118:4454.
  61. Liu D, Zhang X, Yu L, et al. KLF1 mutations are relatively more common in a thalassemia endemic region and ameliorate the severity of β-thalassemia. Blood 2014; 124:803.
  62. Bunn HF, Briehl RW. The interaction of 2,3-diphosphoglycerate with various human hemoglobins. J Clin Invest 1970; 49:1088.
  63. Ranney HM, Lam R, Rosenberg G. Some properties of hemoglobin A2. Am J Hematol 1993; 42:107.
  64. Nagel RL, Bookchin RM, Johnson J, et al. Structural bases of the inhibitory effects of hemoglobin F and hemoglobin A2 on the polymerization of hemoglobin S. Proc Natl Acad Sci U S A 1979; 76:670.
  65. Ducrocq R, Bennani M, Bellis G, et al. Hemoglobinopathies in the Dogon Country: presence of beta S, beta C, and delta A' genes. Am J Hematol 1994; 46:245.
  66. Allen DW, Schroeder WA, Balog J. Observations on the chromatographic heterogeneity of normal adult and fetal human hemoglobins. J Am Chem Soc 1958; 80:1628.
  67. McDonald MJ, Shapiro R, Bleichman M, et al. Glycosylated minor components of human adult hemoglobin. Purification, identification, and partial structural analysis. J Biol Chem 1978; 253:2327.
  68. Garlick RL, Mazer JS, Higgins PJ, Bunn HF. Characterization of glycosylated hemoglobins. Relevance to monitoring of diabetic control and analysis of other proteins. J Clin Invest 1983; 71:1062.
  69. Bookchin RM, Gallop PM. Structure of hemoglobin AIc: nature of the N-terminal beta chain blocking group. Biochem Biophys Res Commun 1968; 32:86.
  70. Bunn HF, Haney DN, Gabbay KH, Gallop PM. Further identification of the nature and linkage of the carbohydrate in hemoglobin A1c. Biochem Biophys Res Commun 1975; 67:103.
  71. Bunn HF, Gabbay KH, Gallop PM. The glycosylation of hemoglobin: relevance to diabetes mellitus. Science 1978; 200:21.
  72. Nathan DM, Singer DE, Hurxthal K, Goodson JD. The clinical information value of the glycosylated hemoglobin assay. N Engl J Med 1984; 310:341.
  73. Makita Z, Vlassara H, Rayfield E, et al. Hemoglobin-AGE: a circulating marker of advanced glycosylation. Science 1992; 258:651.
  74. Brownlee M. Lilly Lecture 1993. Glycation and diabetic complications. Diabetes 1994; 43:836.
  75. Prome D, Blouquit Y, Ponthus C, et al. Structure of the human adult hemoglobin minor fraction A1b by electrospray and secondary ion mass spectrometry. Pyruvic acid as amino-terminal blocking group. J Biol Chem 1991; 266:13050.
  76. Little RR, Roberts W. A review of variant hemoglobins interfering with Hemoglobin A1c. Measurement J Diabetes Sci Technol 2009; 3.
  77. Flückiger R, Harmon W, Meier W, et al. Hemoglobin carbamylation in uremia. N Engl J Med 1981; 304:823.
  78. Stevens VJ, Fantl WJ, Newman CB, et al. Acetaldehyde adducts with hemoglobin. J Clin Invest 1981; 67:361.
  79. Hoberman HD. Post-translational modification of hemoglobin in alcoholism. Biochem Biophys Res Commun 1983; 113:1004.