Cellular life is reliant upon rapid and efficient responses to internal and external conditions. The basic molecular events associated with these processes are the structural transitions of the proteins (structural protein allostery) involved. From this view, the human hemoglobin (Hb) molecule (α 2β 2) holds a special position in this field. Hb has two types of αβ interface ( i.e., α 1β 1 [and α 2β 2] and α 1β 2 [and α 2β 1]). The latter α 1–β 2 (and α 2–β 1) interface is known to be associated with cooperative O 2 binding, and exhibits principal roles if the molecule goes from its deoxy to oxy quaternary structure. However, the role of the former α 1–β 1 (and α 2–β 2) interface has been unclear for a long time. In this regard, important and intriguing observations have been accumulating. A new role was attributed first as stabilizing the HbO 2 tetramer against acidic autoxidation. That is, the α 1–β 1 (and α 2–β 2) interface produces a conformational constraint in the β chain whereby the distal (E7) histidine (His) residue is tilted slightly away from the bound O 2 so as to prevent proton-catalyzed displacement of O 2 – by a solvent water molecule. The β chains thus acquire pH-dependent delayed autoxidation in the HbO 2 tetramer. The next role was suggested by our studies searching for similar phenomena in normal human erythrocytes under mild heating. Tilting of the distal (E7) His in turn triggered degradation of the Hb molecule to hemichrome, and subsequent clustering of Heinz bodies within the erythrocyte. As Heinz body-containing red cells become trapped in the spleen, it was demonstrated that the α 1–β 1 (and α 2–β 2) interface may exert delicate control of the fate (removal) of its own erythrocyte. Herein we review and summarize the related results and current interpretation of the oxidative behavior of human Hb, emphasizing the correlation between hemichrome emergence and Heinz-body formation, and specifically discuss the new roles assigned to the α 1–β 1 (and α 2–β 2) interface. The α 1–β 1 (and α 2–β 2) interface seems to adequately differentiate between the two types of function (dual roles) from physiological to cellular.
References
[1]
Paul, W.D.; Kemp, C.R. Methemoglobin: A normal constituent of blood. Proc. Soc. Exp. Biol. Med. 1944, 56, 55–56.
[2]
Bodansky, O. Methemoglobinemia and methemoglobin-producing compounds. Pharmacol. Rev. 1951, 3, 144–196.
[3]
Scott, E.M.; Duncan, I.W.; Ekstrand, V. The reduced pyridine nucleotide dehydrogenases of human erythrocytes. J. Biol. Chem. 1965, 240, 481–485.
[4]
Hultquist, D.E.; Passon, P.G. Catalysis of methemoglobin reduction by erythrocyte cytochrome b5 and cytochrome b5 reductase. Nature 1971, 229, 252–254.
[5]
Sugita, Y.; Nomura, S.; Yoneyama, Y. Purification of reduced pyridine nucleotide dehydrogenase from human erythrocytes and methemoglobin reduction by the enzyme. J. Biol. Chem. 1971, 246, 6072–6078.
[6]
Rachmilewitz, E.A.; Peisach, J.; Bradley, T.B.; Blumberg, W.E. Role of haemichromes in the formation of inclusion bodies in haemoglobin H disease. Nature 1969, 222, 248–250.
[7]
Rachmilewitz, E.A.; Peisach, J.; Blumberg, W.E. Studies on the stability of oxyhemoglobin A and its constituent chains and their derivatives. J. Biol. Chem. 1971, 246, 3356–3366.
[8]
Rachmilewitz, E.A. Denaturation of the normal and abnormal hemoglobin molecule. Semin. Hematol. 1974, 11, 441–462.
[9]
Winterboun, C.C.; Carrell, R.W. Studies of hemoglobin denaturation and Heinz body formation in the unstable hemoglobin. J. Clin. Invest. 1974, 54, 678–689.
[10]
Macdonald, V.W. Measuring relative rates of hemoglobin oxidation and denaturation. Methods Enzymol. 1994, 231, 480–490.
[11]
Rifkind, J.M.; Abugo, O.; Levy, A.; Heim, J. Detection, formation, and relevance of hemichromes and hemochromes. Methods Enzymol. 1994, 231, 449–480.
[12]
Brooks, J. The oxidation of haemoglobin to methaemoglobin by oxygen. Proc. Roy. Soc. London Ser. B 1931, 109, 35–50.
[13]
Brooks, J. The oxidation of haemoglobin to methaemoglobin by oxygen II—The relation between the rate of oxidation and the partial pressure of oxygen. Proc. Roy. Soc. London Ser. B 1935, 118, 560–570.
[14]
Mansouri, A.; Winterhalter, K.H. Nonequivalence of chains in hemoglobin oxidation. Biochemistry 1973, 12, 4946–4949.
[15]
Tomoda, A.; Yoneyama, Y.; Tsuji, A. Changes in intermediate haemoglobins during autoxidation of haemoglobin. Biochem. J. 1981, 195, 485–492.
[16]
Sugawara, Y.; Sakoda, M.; Shibata, N.; Sakamoto, H. Autoxidation of human hemoglobin: Kinetic analysis of the pH-profile. Jpn. J. Phys. 1993, 43, 21–34.
[17]
Tsuruga, M.; Matsuoka, A.; Hachimori, A.; Sugawara, Y.; Shikama, K. The molecular mechanism of autoxidation for human oxyhemoglobin: Tilting of the distal histidine causes nonequivalent oxidation in the β chain. J. Biol. Chem. 1998, 273, 8607–8615.
[18]
Yasuda, J.-P.; Ichikawa, T.; Tsuruga, M.; Matuoka, A.; Sugawara, Y.; Shikama, K. The α1β1 contact of human hemoglobin plays a key role in stabilizing the bound dioxygen: Further evidence from the iron valency hybrids. Eur. J. Biochem. 2002, 269, 202–211.
[19]
Brunori, M.; Falcioni, G.; Fioretti, E.; Giardina, B.; Rotilio, G. Formation of superoxide in the autoxidation of the isolated α and β chains of human hemoglobin and its involvement in hemichrome precipitation. Eur. J. Biochem. 1975, 53, 99–104.
[20]
Sugawara, Y.; Kadono, E.; Suzuki, A.; Yukuta, Y.; Shibasaki, Y.; Nishimura, N.; Kameyama, Y.; Hirota, M.; Ishida, C.; Higuchi, N.; Haramoto, K.; Sakai, Y.; Soda, H. Hemichrome formation observed in human haemoglobin A under various buffer conditions. Acta. Physiol. Scand. 2003, 179, 49–59.
[21]
Winslow, R.M.; Anderson, W.F. The Hemoglobinopathies. In The Metabolic Basis of Inherited Disease; Stanbury, J.B., Wyngaarden, J.B., Fredricks, D.S., Eds.; McGraw-Hill Book Company: New York, NY, USA, 1978; pp. 1465–1507.
[22]
Weatherall, D.J.; Clegg, J.B.; Higgs, D.R.; Wood, W.G. The Hemoglobinopathies. In The Metabolic and Molecular Basis of Inherited Disease; Scriver, C.R., Beaudet, A.L., William, S.S., Valle, D., Eds.; McGraw-Hill Inc.: New York, NY, USA, 1995; Volume III, pp. 3413–3484.
[23]
Sugawara, Y.; Abe, Y.; Ohgushi, I.; Ueno, E.; Shimamoto, F. Roles of innate instability characteristic of hemoglobin molecule to hemichrome and subsequent Heinz body formation within normal human erythrocytes. Res. Rev. Biosci. 2009, 3, 204–215.
[24]
Sugawara, Y.; Hayashi, Y.; Shigemasa, Y.; Abe, Y.; Ohgushi, I.; Ueno, E.; Shimamoto, F. Molecular biosensing mechanisms in the spleen for the removal of aged and damaged red cells from the blood circulation. Sensors 2010, 3, 7099–7121.
[25]
Jacob, H.S. Mechanisms of Heinz body formation and attachment red cell membrane. Semin. Hematol. 1970, 7, 341–353.
[26]
Vitagliano, L.; Vergara, A.; Bonomi, G.; Merlino, A.; Verde, C.; Prisco, G.D.; Howes, B.D.; Smulevich, G.; Mazzarella, L. Spectroscopic and crystallographic characterization of a tetrameric hemoglobin oxidation reveals structural features of the functional intermediate relaxed/tense state. J. Am. Chem. Soc. 2008, 130, 10527–10535.
[27]
Hermans, J., Jr.; Rialdi, G. Heat of ionization and denaturation of sperm-whale myoglobin determined with a microcalorimeter. Biochemistry 1965, 4, 1277–1281.
[28]
Fasman, G.D. Physical and chemical data. In Handbook of Biochemistry and Molecular Biology, 3rd ed. ed.; CRC Press: Cleveland, OH, USA, 1976; p. 220.
[29]
McDonald, M.J.; Turci, S.M.; Mrabet, N.T.; Himelstein, B.P.; Bunn, H.F. The kinetics of assembly of normal and variant human oxyhemoglobin. J. Biol. Chem. 1987, 262, 5951–5956.
[30]
Tomoda, A.; Sugimoto, K.; Suhara, M.; Takeshita, M.; Yoneyama, Y. Haemichrome formation from haemoglobin subunits by hydrogen peroxide. Biochem. J. 1978, 171, 329–335.
[31]
Tomoda, A.; Takeshita, M.; Yoneyama, Y. Characterization of intermediate hemoglobin produced during methemoglobin reduction by ascorbic acid. J. Biol. Chem. 1978, 253, 7415–7419.
[32]
Tomoda, A.; Tsuji, A.; Matsukawa, S.; Takeshita, M.; Yoneyama, Y. Mechanism of methemoglobin reduction by ascorbic acid under anaerobic conditions. J. Biol. Chem. 1978, 253, 7420–7423.
[33]
Tomoda, A.; Yubisui, T.; Tsuji, A.; Yoneyama, Y. Kinetic studies on methemoglobin reduction by human red cell NADH cytochrome b5 reductase. J. Biol. Chem. 1979, 254, 3119–3123.
[34]
Tomoda, A.; Yubisui, T.; Tsuji, A.; Yoneyama, Y. Analysis of met-form haemoglobin in human erythrocytes of normal adults and of a patient with hereditary methaemoglobinaemia due to deficiency of NADH-cytochrome b5 reductase. Biochem. J. 1979, 181, 505–507.
[35]
Tomoda, A.; Tsuji, A.; Yoneyama, Y. Mechanism of hemoglobin oxidation by ferricytochrome c under aerobic and anaerobic conditions. J. Biol. Chem. 1980, 255, 7978–7983.
[36]
Tomoda, A.; Ida, M.; Tsuji, A.; Yoneyama, Y. Mechanism of methemoglobin reduction by human erythrocytes. Biochem. J. 1980, 188, 535–540.
[37]
Sugawara, Y.; Matsuoka, A.; Kaino, A.; Shikama, K. Roles of globin moiety in the autoxidation reaction of oxymyoglobin: Effect of 8 M urea. Biophys. J. 1995, 69, 583–592.
[38]
Demetriou, J.A.; Drewes, P.A.; Gin, J.B. Enzymes. In Clinical Chemistry, 2nd ed.; Henry, R.J., Cannon, D.C., Winkelmann, J.W., Eds.; Harper & Row Publishers: New York, NY, USA, 1974; pp. 815–1001.
[39]
Bauer, J.D. Laboratory investigation of hemoglobin. In Gradwohl's Clinical Laboratory Methods and Diagnosis; Sonnenwirtyh, A.C., Jarett, L., Eds.; The C V Mosby Company: ST Louis, MO, USA, 1980; pp. 809–901.
[40]
Kikuchi, Y.; Sato, K.; Ohki, H.; Kaneko, T. Optically accessible microchannels formed in a single-crystal silicon substrate for studies of blood rheology. Microvasc. Res. 1992, 44, 226–240.
[41]
Suganuma, H.; Inakuma, T.; Kikuchi, Y. Amelioratory effect of barley tea drinking on blood fluidity. J. Nutr. Sci. Vitaminol. 2002, 48, 165–182.
[42]
Begum, A.N.; Terao, J. Protective effect of quercetin against cigarette tar extract-induced impairment of erythrocyte deformability. J. Nutri. Biochem. 2002, 13, 265–272.
[43]
Kamada, H.; Hattori, K.; Hayashi, T.; Suzuki, K. In vitro evaluation of blood coagulation activation and microthrombus formation by a microchannel array flow analyzer. Thromb. Res. 2004, 114, 195–203.
[44]
Sumino, H.; Nara, M.; Seki, K.; Takahashi, T.; Kanda, T.; Ichikawa, S.; Goto-Onozato, K.; Koya, S.; Murakami, M.; Kurabayashi, M. Effect of antihypertensive therapy on blood rheology in patients with essential hypertension. J. Int. Med. Res. 2005, 33, 170–177.
[45]
Watanabe, N.; Kimura, F.; Kojima, F.; Endo, Y.; Fujimoto, K.; Kikuchi, Y. Effect of sterols in dietary fats on whole blood viscosity of stroke-prone spontaneously hypertensive rats (SHRSP). J. Oleo. Sci 2005, 54, 1–6.
[46]
Muranaka, Y.; Kunimoto, F.; Takita, J.; Sumino, H.; Nara, M.; Kuwano, H.; Murakami, M. Impaired blood rheology in critically ill patients in an intensive care unit. J. Int. Med. Res. 2006, 34, 419–427.
[47]
Seki, K.; Sumino, H.; Nara, M.; Ishiyama, N.; Nishino, M.; Murakami, M. Relationships between blood rheology and age, body mass index, blood cell count, fibrinogen, and lipids in healthy subjects. Clin. Hemorheol. Microcirc. 2006, 34, 401–410.
[48]
Watanabe, N.; Watanabe, Y.; Kumagai, M.; Fujimoto, K. Administration of dietary fish oil capsules in healthy middle-aged Japanese men with a high level of fish consumption. Int. J. Food Sci. Nutr. 2009, 60, 136–142.
[49]
Perutz, M.F. Stereochemistry of cooperative effects in haemoglobin. Nature 1970, 228, 726–739.
[50]
Perutz, M.F. Nature of haem-haem interaction. Nature 1972, 237, 495–499.
[51]
Perutz, M.F; Fermi, G.; Abraham, D.J.; Poyart, C.; Bursaux, E. Hemoglobin as a receptor of drugs and peptides: X-ray studies of the stereochemistry of binding. J. Am. Chem. Soc. 1986, 108, 1064–1078.
[52]
Imai, K. Adair fitting to oxygen equilibrium curves of hemoglobin. Methods Enzymol. 1994, 232, 559–576.
[53]
Baldwin, J.; Chothia, C. Haemoglobin: The structural changes related to ligand binding and its allosteric mechanism. J. Mol. Biol. 1979, 129, 175–220.
[54]
Fermi, G.; Perutz, M.F. Haemoglobin and Myoglobin. In Atlas of Molecular Structure in Biology; Phillips, D.C., Richards, F.M., Eds.; Clarendon Press: Oxford, UK, 1981; Volume 2.
[55]
Dickerson, R.E.; Geis, I. Hemoglobin: Structure, Function, Evolution and Pathology; The Benjamin/Cummings Publishing Co., Inc.: Menlo Park, CA, USA, 1983.
[56]
Perutz, M.F. Mechanisms of Cooperativity and Allosteric Regulation in Proteins; Cambridge University Press: Cambridge, UK, 1990.
[57]
Perutz, M.F.; Wilkinson, A.J.; Paoli, M.; Dodson, G.G. The stereochemical mechanism of the cooperative effects in hemoglobin revisited. Annu. Rev. Biophys. Biomol. Struct. 1998, 27, 1–34.
[58]
Borgstahl, G.E.O.; Rogers, P.H.; Arnone, A. The 1.8 ？ structure of carbonmonoxy-β4 hemoglobin. J. Mol. Biol. 1994, 236, 817–830.
[59]
Levy, A.; Sharma, V.S.; Zhang, L.; Rifkind, J.M. A new mode for heme-heme interaction in hemoglobin associated with distal perturbations. Biophys. J. 1992, 61, 750–755.
[60]
Shikama, K. Nature of the FeO2 bonding in myoglobin: An overview from physical to clinical. Experientia 1985, 41, 701–706.
[61]
Shikama, K. Stability properties of dioxygen-iron (II) porphyrins: An overview from simple complexes to myoglobin. Coord. Chem. Rev. 1988, 83, 73–91.
[62]
Shikama, K. Autoxidation of oxymyoglobin: A meeting point of the stabilixation and the activation of molecular oxygen. Biol. Rev. 1990, 65, 517–527.
[63]
Shikama, K. The molecular mechanism of autoxidation for myoglobin and hemoglobin: A venerable puzzle. Chem. Rev. 1998, 98, 1357–1373.
[64]
Shikama, K. Nature of the FeO2 bonding in myoglobin and hemoglobin: A new molecular paradigm. Prog. Biophys. Mol. Biol. 2006, 91, 83–162.
[65]
Kao, O.H.W.; Wang, J.H. Kinetic study of the oxidation of ferrohemochrome by molecular oxygen. Biochemistry 1965, 4, 342–347.
[66]
Park, S.-Y.; Yokoyama, T.; Shibayama, N.; Shiro, Y.; Tame, J.R.H. 1.25 ？ resolution crystal structure of human haemoglobin in the oxy, deoxy and carbonmonooxy forms. J. Mol. Biol. 2006, 360, 690–701.
[67]
Jandel, J.H.; Engle, L.K.; Allen, D.W. Oxidative hemolysis and precipitation of hemoglobin. I. Heinz body anemias as an acceleration of red cell aging. J. Clin. Invest. 1960, 39, 1818–1836.
[68]
Peisach, J.; Blumberg, W.E.; Rachmilewitz, E.A. Detection of formation, and relevance of hemichromes and hemochromes. Biochim. Biophys. Acta 1975, 393, 404–418.
[69]
Sears, D.A.; Friedman, J.M.; White, D.R. Binding of intracellular protein to the erythrocyte membrane during incubation: The production of Heinz bodies. J. Lab. Clin. Med. 1975, 86, 722–732.
[70]
Campwala, H.Q.; Desforges, J.F. Membrane-bound hemichrome in density-separated cohorts of normal (AA) and sickled (SS) cells. J. Lab. Clin. Med. 1982, 99, 25–28.
[71]
Selwyn, J.G. Heinz bodies in red cells after splenectomy and after phenacetin administration. Br. J. Hematol. 1955, 1, 173–183.
[72]
Weiss, L. The structure of fine splenic arterial vessels in relation to hemoconcentration and red cell destruction. Am. J. Anat. 1962, 111, 131–179.
[73]
Weiss, L. The structure of intermediate vascular pathways in the spleen of rabbits. Am. J. Anat. 1963, 113, 51–59.
[74]
Wennberg, E.; Weiss, L. Splenic erythroclasia: An electron microscopic study of hemoglobin H disease. Blood 1968, 31, 778–790.
[75]
Phillips, S.E.V. Structure of oxymyoglobin. Nature 1978, 273, 247–248.
[76]
Vitagliano, L.; Bonomi, G.; Riccio, A.; Prisco, G.D.; Smulevich, G.; Mazzarella, L. The oxidation process of Antarctic fish hemoglobins. Eur. J. Biochem. 2004, 271, 1651–1659.
[77]
Vergara, A.; Franzese, M.; Merlino, A.; Vitagliano, L.; Verde, C.; Prisco, G.D.; Lee, H.C.; Peisach, J.; Mazzarella, L. Structural characterization of ferric hemoglobins from three Antarctic fish species of the suborder notothenioidei. Biophys. J. 2007, 93, 2822–2829.
[78]
Vergara, A.; Franzese, M.; Merlino, A.; Bonomi, G.; Verde, C.; Giordano, D.; Prisco, G.D.; Lee, H.C.; Peisach, J.; Mazzarella, L. Correlation between hemichrome stability and the root effect in tetrameric hemoglobins. Biophys. J. 2009, 97, 866–874.
[79]
Robinson, V.L.; Smith, B.B.; Arnone, A. A pH-dependent aquomet-to-hemichrome transition in crystalline horse methemoglobin. Biochemistry 2003, 42, 10113–10125.
[80]
Clark, M.R. Senescence of red blood cells: Progress and problems. Physiol. Rev. 1988, 68, 503–554.
[81]
Low, P.S. Role of Hemoglobin Denaturation and Band 3 Clustering in Initiating Red Cell Removal. In Red Blood Cell Aging; Magnani, M., De Flora, A., Eds.; Plenum Press: New York, NY, USA, 1991; pp. 173–183.
[82]
Walder, J.A.; Chatterjee, R.; Steck, T.L.; Low, P.S.; Musso, G.F.; Kaiser, E.T.; Rogers, P.H.; Arnone, A. The interaction of hemoglobin with the cytoplasmic domain of band 3 of the human erythrocyte membrane. J. Biol. Chem. 1984, 259, 10238–10246.
[83]
Waugh, S.M.; Low, P. S Hemichrome binding to band 3: Nucleation of Heinz bodies on the erythrocyte membrane. Biochemistry 1985, 24, 34–39.
[84]
Low, P.S.; Waugh, S.M. The role of hemoglobin denaturation and band 3 clustering in red blood cell aging. Science 1985, 227, 531–533.
[85]
Schlueter, K.; Drenckhahn, D. Co-clustering of denatured hemoglobin with band 3: Its role in binding of autoantibodies against band 3 to abnormal and aged erythrocytes. Proc. Natl. Acad. Sci. USA 1986, 83, 6137–6141.
[86]
Waugh, S.M.; Walder, J.A.; Low, P.S. Partial characterization of the copolymerization reaction of erythrocyte membrane band 3 with hemichromes. Biochemistry 1987, 26, 1777–1783.
[87]
Ende, J.V.D.; Coppena, G.; Verstraeten, T.; Haegenborgh, T.V.; Depraetere, K.; Gompel, A.V.; Enden, E.V.D.; Clerinx, J.; Colebunders, R.; Peetermans, W.E.; et al. Recurrence of blackwater fever: triggering relapses by different antimararials. Trop. Med. Inter. Health. 1998, 3, 632–639.
[88]
White, J.M. Mararia. In Manson's Tropical Diseases; Cook, G.C., Zumura, A.I., Eds.; W.B. Saunders: Philadelphia, PA, USA, 2003; pp. 1205–1295.
[89]
Hue, N.T.; Charlieu, J.P.; Chau, T.T.H.; Day, N.; Farra, J.J.; Hien, T.T.; Dunstan, S.J. Glucose-6-phosphate dehydrogenase (G6PD) mutations and Haemoglobinuria syndrome in the Vietnamese population. Malaria J. 2009, 8, 152–160.
