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Oxygen Equilibria of Hemoglobin A2 and Hemoglobin Lepore

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Oxygen Equilibria of Hemoglobin A2 and Hemoglobin Lepore Oxygen Equilibria of Hemoglobin A2 and Hemoglobin Lepore Grace G. Eddison, … , Robin W. Briehl, Helen M. Ranney J Clin Invest. 1964;43(12):2323-2331. https://doi.org/10.1172/JCI105106. Research Article Find the latest version: https://jci.me/105106/pdf Journal of Clinical Investigation Vol. 43, No. 12, 1964 Oxygen Equilibria of Hemoglobin A2 and Hemoglobin Lepore * GRACE G. EDDISON,t ROBIN W. BRIEHL,$ AND HELEN M. RANNEY (From the Departments of Medicine and Physiology of the Albert Einstein College of Medi- cine and the Bronx Municipal Hospital Center, New York, N. Y.) Human hemoglobin provides a model for studies the oxygen equilibria of erythrocytes obtained concerned with the relationships of structure and from an adult in whom hemoglobin F comprised biologic function of proteins. Older evidence for 69%o of the total pigment resembled the oxygen conformational differences between oxygenated equilibria of normal adult blood rather than that and deoxygenated normal hemoglobin (1) has of cord blood. These workers (8) suggested that recently been confirmed and extended by X-ray differences between the fetal and adult red cell crystallographic studies (2) and by comparison of other than the type of hemoglobin must be con- the dissociation (3) and of the hybridization (4) cerned in the oxygenation function of whole blood of the oxygenated and deoxygenated pigments. obtained from newborn infants. Normal and abnormal human hemoglobins have Although hemolysates containing large pro- been utilized in the past by other workers for in- portions of hemoglobins F or A can be studied di- vestigation of relationships between structure and rectly, isolation procedures must be utilized to oxygen equilibria. Some of these observations, achieve appropriate concentrations of some of the grouped on the basis of the structure of the he- minor components. For example, since hemo- moglobins studied, are briefly cited below. globin A, (a2A SA2) accounts for only 5 or 6%o 1) Normal human, hemoglobins A (aA p2A), of the hemoglobin of subjects with thalassemia F (a,2A 'F), and A. (a2A 8A-) are tetramers con- minor, for functional studies at least partial iso- taining apparently identical aA polypeptide chains, lation of hemoglobin A, is required. Rossi- but differing in the non-alpha chains. Extensive Fanelli, Antonini, Benerecetti, and De Marco (9) studies of the oxygen equilibria of hemolysates pre- isolated hemoglobins A and A2 electrophoretically pared from the erythrocytes of normal subjects and found no significant difference in the oxygen and of normal erythrocytes, containing almost dissociation curves. Meyering, Israels, Sebens, entirely hemoglobin A, provide values with which and Huisman (10) and Huisman, Dozy, Necht- data on other human hemoglobins may be com- man, and Thompson (11), however, employed pared. The increased oxygen affinity observed column chromatography for separations and found in the whole blood of newborn infants (5, 6) can- that hemoglobin A, exhibited increased oxygen not be due solely to the presence of hemoglobin F, affinity as compared with hemoglobin A. since solutions of hemoglobin F and of hemo- 2) Abnormal hemoglobins with single amino globin A exhibit the same oxygen dissociation acid substitutions. The functions of some of the curves (7, 8). Furthermore, in the studies of abnormal hemoglobins that result from single Schruefer, Heller. Battaglia, and Hellegers (8), amino acid substitutions in one pair of polypep- tide chains have been studied. Among these are * Submitted for publication June 23, 1964; accepted 6 August 10, 1964. pl-chain variants, hemoglobin S (a2A 2 val), he- Supported by grant G-6357 from the Life Insurance moglobin C (a2A /326lYs), hemoglobin DO, and an Medical Research Fund, grant A-4502 from the Na- a-chain variant, hemoglobin I. Although de- tional Institute of Arthritis and Metabolic Diseases, and creased oxygen affinity has been observed in whole grant HE-07451 from the National Heart Institute. blood from with sickle cell anemia t Recipient of fellowship (no. 5-F2-HE-18,557) from patients (12- the National Heart Institute. 15), data concerning the oxygen affinity of solu- t Career scientist of the Health Research Council of tions of hemoglobins S are conflicting (16). It the City of New York. seems probable, however, that large differences in 2323 2324 G. G. EDDISON, R. W. BRIEHL, AND H. M. RANNEY oxygen affinity do not exist for hemolysates of 4) Hemoglobin Lepore. The structure of he- hemoglobins A and S (8, 17, 18). No difference moglobin Lepore, as elucidated by Baglioni (23), in the oxygen affinities of hemoglobins C and A represents a hitherto unrecognized class of he- has been observed in two studies (4, 18), but small moglobin abnormalities: normal a chains com- increases in oxygen affinity for two hemoglobin D bined with chains that are products of unequal variants have been reported (18). Hemoglobin crossing over in the linked 8-,8 locus. Thus he- I, an a-chain variant, had a normal oxygen moglobin Lepore contains apparently normal aA equilibrium (4). In the M hemoglobins in which chains and non-alpha chains, which include initial oxidized heme iron is present in either the a or peptides of 8 chains and the remaining peptides ,f polypeptide chains, there is obvious interference from the ft-chain sequence. Hemoglobin Lepore with the oxygenation function; Kiese, Kurz, and may be designated a2A x2, where x represents Schneider (19) have reported a case in which en- the chain resulting from the crossing over. Since zymatic reduction of hemoglobin M yielded a he- crossing over may occur at different sites, dif- moglobin with a normal oxygen affinity. Reiss- ferent examples of hemoglobin Lepore might ex- mann, Ruth, and Nomura (20) described an un- hibit different lengths of 8 (or f) sequence. Huis- usual abnormal hemoglobin with a low oxygen man, Still, and Nechtman noted an increased oxy- affinity; no structural studies of the pigment were gen affinity in an example of hemoglobin Lepore included in the report. (18). 3) Tetramers of one type of polypeptide chain. Thus, apart from certain special cases, e.g., Studies of functional properties of hemoglobins the hemoglobin studied by Reissmann and co- that are tetramers of one variety of polypeptide workers (20), hemoglobins that are tetramers chain, i.e., H (ft4A) and Bart's (74F), have dis- containing two a chains linked to two or to two closed striking abnormalities. Both hemoglobin y chains exhibit nearly the same oxygen affinity H (21) and Bart's (22) exhibit extraordinarily as does hemoglobin A. Data concerning the oxy- high oxygen affinities and absence of heme-heme gen affinity of hemoglobin A2 are conflicting (9- interaction, and neither has a significant Bohr 11). effect. It has therefore been suggested that in- The present studies were undertaken to re- teractions between a and chains are necessary investigate the oxygen function of hemoglobin A2 for these three aspects of hemoglobin function and to study the functional properties of another (21). example of hemoglobin Lepore. TABLE I Data from which the statistical analyses were calculated Hemoglobin A Hemoglobin A Whole hemolysate concentration equiv- Isolated concentration equiv- Isolated Normal whole containing hemo- alent to hemo- hemoglobin alent to hemo- hemoglobin hemolysate globin Lepore globin Lepore Lepore globin A2 A2 log Po0 pH log Pso pH log Pso pH log Ps0 pH log Ps0 pH log P50 pH 0.903 7.07 0.875 7.07 0.826 7.00 0.740 6.82 0.813 7.02 0.820 7.00 0.940 7.07 0.903 7.07 0.833 7.00 0.742 6.82 0.820 7.02 0.839 7.00 0.813 7.20 0.839 7.19 0.820 7.00 0.663 7.00 0.699 7.20 0.732 7.19 0.813 7.20 0.839 7.19 0.740 7.18 0.690 7.00 0.708 7.20 0.716 7.19 0.690 7.46 0.681 7.44 0.763 7.18 0.699 7.02 0.623 7.40 0.748 7.21 0.690 7.46 0.681 7.44 0.778 7.22 0.556 7.10 0.623 7.40 0.748 7.21 0.586 7.62 0.550 7.62 0.732 7.22 0.556 7.10 0.544 7.50 0.580 7.42 0.544 7.63 0.538 7.62 0.568 7.44 0.602 7.20 0.544 7.50 0.574 7.42 0.544 7.63 0.586 7.44 0.602 7.20 0.525 7.55 0.519 7.57 0.643 7.22 0.519 7.55 0.525 7.57 0.643 7.22 0.505 7.38 0.512 7.38 0.498 7.40 0.512 7.40 0.380 7.58 0.423 7.58 OXYGEN EQUILIBRIA OF HEMOGLOBIN A2 AND HEMOGLOBIN LEPORE 2325 A. Methods 100rI 9%__ 1) Preparation of hemoglobin compoeic)tts. Blood I o----Normal whole Hemolysate samples were collected in 3.2% sodium citrate from an male of Italian 901- -Whole Hemolysate containing Lepore 1) 18-year-old ancestry, heterozygous // for hemoglobin LeporeEinstein (24),' for isolation of he- 80 / moglobin Lepore (which comprised 12% of the total A/ pigment), 2) a 58-year-old woman of Italian ancestry with thalassemia minor, in whom hemoglobin A2 com- 70-70-/I prised 6% of the hemoglobin, for isolation of hemoglobin /1 A2, and 3) normal subjects, for preparation of control 60_ hemoglobin A samples. Hemolysates containing hemo- / l globin in concentrations of 10 g per 100 ml were pre- 50, pared by the method of Drabkin (25). Samples of % 02 hemoglobin Lepore and of hemoglobin A2 were prepared from the appropriate hemolysate by electrophoresis in 40- / 0.05 M Veronal buffer on starch granules or on Pevikon / / (26) by the method of Kunkel, Ceppellini, Milller-Eber- and Wolf 30_ / / hard, (27).
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