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PubMed1978

Oxidation-reduction reactions of hemoglobin A, hemoglobin M Iwate, and hemoglobin M Hyde Park.

The kinetics and equilibrium of the redox reactions of hemoglobin A, hemoglobin M Iwate, and hemoglobin M Hyde Park using the iron (II) and iron (III) complexes of trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetate (CDTA4-) as the reducing and oxidizing agents have been studied. With respect to the equilibrium it was found that hemoglobin M Iwate (where the beta chains were reduced) was more readily reduced than hemoglobin M Hyde Park (where the alpha chains are reduced). This difference was shown to be a result of a difference in the rate constant for reduction but not oxidation. The observed rate contants for the reduction of all three hemoglobins were shown to decrease with increasing pH. This was attributed to a decrease in the [T]/[R] ratio. The observed rate contants for the oxidation reaction were shown to increase with increasing pH. Accompanying this increase was a change in the kinetic profile for hemoglobin A from pseudo first order to one in which the rate increased as the extent of reaction increased. Inositol hexaphosphate had no effect on the rate of oxidation of deoxyhemoglobin A. This was a result of binding of FeCDTA2- or HCDTA3- to the protein. However, in the presence of inositol hexaphosphate, the reduction of methemoglobin A exhibited biphasic kinetics. This result was interpreted in terms of the production of a small amount of a conformation which was more readily reduced.

Hemoglobin A↗
PubMed1995

Allosteric modulation by tertiary structure in mammalian hemoglobins. Introduction of the functional characteristics of bovine hemoglobin into human hemoglobin by five amino acid substitutions.

Bovine erythrocytes do not contain 2,3-diphosphoglycerate, the principal allosteric effector of human hemoglobin. Bovine hemoglobin has a lower oxygen affinity than human hemoglobin and is regulated by physiological concentrations of chloride (Fronticelli, C., Bucci, E., and Razynska, A. (1988) J. Mol. Biol. 202, 343-348). It has been proposed that the chloride regulation in bovine hemoglobin is introduced by particular amino acid residues located in the amino-terminal region of the A helix and in the E helix of the beta subunits (Fronticelli, C. (1990) Biophys. Chem. 37, 141-146). In accordance with this proposal we have constructed two mutant human hemoglobins, beta(V1M+H2deleted+T4I+P5A) and beta(V1M+H2deleted+T4I+P5A+A76K). These are the residues present at the proposed locations in bovine hemoglobin except for isoleucine at position 4. Oxygen binding studies demonstrate that these mutations have introduced into human hemoglobin the low oxygen affinity and chloride sensitivity of bovine hemoglobin and reveal the presence of a previously unrecognized allosteric mechanism of oxygen affinity regulation where all the interactions responsible for the lowered affinity and chloride binding appear to be confined to individual beta subunits.

Allosteric Regulation↗
PubMed1992

Immunological effects of hemoglobin, encapsulated hemoglobin, polyhemoglobin and conjugated hemoglobin using different immunization schedules.

Repeated subcutaneous immunizing injections into rats of Freund's adjuvant containing rat hemoglobin or o-raffinose rat polyhemoglobin did not result in increase in IgG antibody titers. However, heterologous hemoglobin injected as above is antigenic (49.50 + 6.70 % CPM). Crosslinking heterologous hemoglobin into o-raffinose polyhemoglobin further increased its antigenicity (75.60 + 4.08). Thus, unlike homologous hemoglobin, cross-linking of heterologous hemoglobin increased its antigenicity. Liposome encapsulated homologous hemoglobin injected subcutaneously with or without Freund's adjuvant did not show antigenicity. Encapsulated heterologous hemoglobin resulted in a minimal increase in antibody titers (10.73 + 4.64) only with Freund's adjuvant, but no increase when injected without Freund's adjuvant. Conjugated heterologous hemoglobin (PEG-Hb) injected intravenously by itself at weekly intervals did not result in significant increase in antibody titers on the 5th week.

Animals↗
PubMed1975

The effects of inositol hexaphosphate on the allosteric properties of two beta-99-substituted abnormal hemoglobins, hemoglobin Yakima and hemoglobin Kempsey.

Hemoglobins (Hb) Yakima and Kempsey were purified from patients' blood with diethylaminoethyl cellulose column chromatography. The oxygen equilibrium curves of the two hemoglobins and the effects of organic phosphates on the function were investigated. In 0.1 M phosphate buffer, Hill's constants n for Hb Yakima and Hb Kempsey were 1.0 to 1.1 at the pH range for 6.5 to 8.0 and the oxygen affinities of both the mutant hemoglobins were about 15 to 20 times that of Hb A at pH 7.0. The Bohr effect was normal in Hb Yakima and one-fourth normal in Hb Kempsey. In the presence of inositol hexaphosphate, the oxygen affinities to Hb Yakima and Hb Kempsey were greatly decreased, and an interesting result revealed that these hemoglobins showed clear cooperativity in oxygen binding. Hill's constant n in the presence of inositol hexaphosphate was 1.9 for Hb Kempsey and 2.3 for Hb Yakima at pH 7.0. The cooperativities of these mutant hemoglobins were pH-dependent, and Hb Kempsey showed high cooperativity at low pH (n equal 2.1 at pH 6.6) and low cooperativity at high pH (n equal 1.0 at pH 8.0). Hb Yakima showed similar pH dependence in cooperativity. In the presence of inositol hexaphosphate, Hb A showed a pH-dependent cooperativity different from those of Hb Yakima and Hb Kempsey, namely, Hill's n was the highest in alkaline pH (n equal 3.0 at pH 8.0) and decreased at lower pH (n equal 1.5 at pH 6.5). 2,3Diphosphoglycerate bound with the deoxygenated Hb Yakima and Hb Kempsey, however, had no effect on the oxygen binding of these abnormal hemoglobin. The pH-dependent cooperativity of alpha1beta2 contact anomalous hemoglobin and normal hemoglobin was explained by the shifts in the equilibrium between the high and low ligand affinity forms.

Allosteric Regulation↗
PubMed1980

[Hemoglobins, XXXIV. "Hemoglobin Heide", a new embryonal hemoglobin. N-terminal sequence of the theta-chains (author's transl)].

A new embryonic hemoglobin is described. Erythrocytes of pig embryos were lysed. The lysate was analyzed by gel-electrophoresis and the hemoglobins were separated on DEAE-Sephacel. The hemoglobin fractions were characterized by sequence analysis. We found in addition a new hemoglobin chain--theta-chain--not yet described. The primary structure of the theta-chains is similar to that of the epsilon-chains. There are only 3 differences in the first 30 residues. Furthermore, these theta-chains were found to be associated with theta-like chains and therefore we propose a hemoglobin of the type x2/theta 2 and we suggest the name "Hemoglobin Heide" for this new embryonic hemoglobin. In conclusion, four different globin gens (alpha-, epsilon-, theta- and theta-gens) and three different hemoglobins (Gower I, Gower II and Hb Heide) were detected in the embryonic respiration of mammals.

Amino Acid Sequence↗
PubMed1975

Allosteric interactions in non-alpha chains isolated from normal human hemoglobin, fetal hemoglobin, and hemoglobin Abruzzo (beta143 (H21) His replaced by Arg).

Oxygen-linked effects of inositol hexaphosphate occur in heme-containing non-alpha chains isolated from normal human hemoglobin, fetal hemoglobin, and the abnormal human hemoglobin Abruzzo, beta143(H21) His leads to Arg. The occurrence of these effects implies that the chains undergo ligand-linked conformational changes. Inositol hexaphosphate lowers the oxygen affinity of isolated beta and gamma chains by differential binding to their deoxy conformations. Neither 2,3-diphosphoglycerate nor inorganic phosphate produces such an effect. In the case of Abruzzo beta chains, the binding of inorganic phosphate and 2,3-diphosphoglycerate is also oxygen-linked. Stripped beta chains isolated from hemoglobin Abruzzo have much higher oxygen affinity than beta chains isolated from HbA. Their higher oxygen affinity and enhanced allosteric interactions with phosphates account, in large part, for the abnormal functional behavior of the hemoglobin Abruzzo tetramer. In this hemoglobin variant the substitution of arginine for histidine at beta143 involves a residue known to interact with anionic allosteric effectors of hemoglobin. It is of interest that the effect of inositol hexaphosphate observed with isolated gamma chains is comparable to the effect observed with isolated beta chains, even though the gamma143 position is occupied by an uncharged serine residue.

Allosteric Regulation↗
PubMed1983

Effect of chloride ion on the oxygen affinity of hemoglobin York (alpha 2 beta 2(146)Pro) and S-York hybrid hemoglobin (alpha 2 beta S beta York). Role of the beta 82 lysyl and beta 146 histydyl residues in chloride binding to hemoglobin.

We estimated the relative role of various chloride binding sites in determining the oxygen affinity of hemoglobin using abnormal hemoglobins such as Hb York (Hb Y) (alpha 2 beta 2(146)Pro), Hb Malmö (Hb M) (alpha 2 beta 2(97)Gln), and Hb S and chemically modified hemoglobins such as cross-linked Hb S, Hb Y, and asymmetrical SY hemoglobin with bis(3,5-dibromosalicyl)fumarate. The chloride effect on the p50 values of Hb S and Hb M was identical to that of Hb A. In contrast, the effect of chloride on the p50 values of Hb Y was only 20% of that of Hb A. Cross-linking between the two beta 82 lysyl residues with fumarate decreased the chloride effect by 40%. The effect of chloride on cross-linked Hb Y, in which both beta 82 lysyl and beta 146 histidyl residues were modified, was unchanged from that on Hb Y (20% of Hb A). The effect of chloride on the p50 value of SY asymmetrical hybrid hemoglobin was 40% of that of Hb A or Hb S, which is midway between the values obtained for cross-linked Hb S and Hb Y. From these results, the contribution of beta 146 His and beta 82 Lys on oxygen affinity by binding of chloride was calculated to be 40% each; the remaining 20% chloride effect was attributed to alpha 1 Val.

Chlorides↗
PubMed1981

[Hemoglobins, XXXVI: The primary structure of a dimeric insect hemoglobin (Erythrocruorin), component IX from Chironomus thummi thummi. Studies on the quarternary structure of the dimeric CTT-hemoglobins (author's transl)].

The primary structure of a dimeric insect hemoglobin (erythrocruorin), component CTT IX (Chironomus thummi thummi) was established by automatic sequence analysis. The alignment of the peptides was facilitated by producing only a few large fragments. The primary structure of CTT IX is compared with the human beta-chains and with CTT III. It is discussed, why for the dimeric CTT-hemoglobins only dimerisation can be observed but no tetramerisation. Experiments were done to locate the binding areas between the subunits in the dimeric molecule. Even after blocking of the alpha-NH2-group by cyanate, the stability of the dimeric molecule is not altered. Therefore the binding regions of the CTT-hemoglobins must be different from those of the tetrameric hemoglobins of vertebrates. Our results lead to a quarternary structure different from that of the hemoglobins of mammalians. This structure explains the possibility of dimerisation, but excludes tetramerisation.

Amino Acid Sequence↗
PubMed1988

Quantification of hemoglobin A2 and identification of hemoglobin variants using a fully automated hemoglobin analyzer.

The DIAMAT Analyser System is a fully automated high performance liquid chromatographic (HPLC) instrument originally designed for the quantification of glycated hemoglobin (HbA1c). Buffers were developed for the separation and quantification of hemoglobin A2 on the DIAMAT. Also studied were the retention patterns of various hemoglobin variants on the DIAMAT using the buffers developed for the hemoglobin A2 quantification.

Adult↗
PubMed1976

Hemoglobin Hope: studies of oxygen equilibrium in heterozygotes, hemoglobin S-Hope disease, and isolated hemoglobin Hope.

Hemoglobin Hope (beta(H14)136gly leads to asp), a mildly unstable variant, was found to have decreased oxygen affinity, a normal Bohr effect and diminished cooperativity. Decreased oxygen affinity of hemoglobin Hope may explain the previous failure to find an appropriate response to hemolysis in individuals studied who were heterozygous for both hemoglobin Hope and sickle hemoglobin. Salt bridge formation between NA1 valine and H14 aspartic acid may stabilize the beta Hope subunit in its deoxy form thus producing intrinsically low oxygen affinity and reduced cooperativity.

Diphosphoglyceric Acids↗
PubMed1984

Involvement of His HC3 (146) beta in the Bohr effect of human hemoglobin. Studies of native and N-ethylmaleimide-treated hemoglobin A and hemoglobin Cowtown (beta 146 His replaced by Leu).

The involvement of the COOH-terminal histidines of the beta chains of human hemoglobin in the allosteric mechanism of oxygen binding has been the topic of intensive discussion. Data presented here on the functional properties of native and chemically modified forms of Hb Cowtown (beta 146 His replaced by Leu) suggest that approximately half of the alkaline Bohr effect is attributable to the imidazole of His HC3(146) beta. The contribution of this residue to the alkaline Bohr effect has been estimated variably as 40-60% and 15% or less. Equilibrium and kinetic studies show that the amino acid substitution in Hb Cowtown decreases the stability of the low affinity conformation, resulting in an increased oxygen affinity and altered sensitivity to anionic effectors. Detailed analysis of Hill plots of oxygen binding according to the Adair scheme reveals that, under conditions of moderate ionic strength (chloride = 0.1 M), the K2 and K3 values for Hb A and Hb Cowtown differ, whereas the K1 and K4 values are closely similar over the physiological pH range. The decreased pH sensitivity of Hb Cowtown is associated with a decreased pH sensitivity of K1, the first Adair constant. In contrast to des-His(146 beta) hemoglobin, the cooperative interactions shown by Hb Cowtown under conditions of moderate ionic strength are not reduced in comparison to those of Hb A. This and the similarity of K1 and K4 values for Hb A and Hb Cowtown indicate that under these conditions the salt bridge formed by the COOH-terminal imidazole group does not significantly contribute to the free energy difference between "T-state" and "R-state" hemoglobin. It appears that the salt bridge formed by the COOH-terminal carboxyl group stabilizes the deoxy, T-state, conformation to a greater degree than previously appreciated. Chemical modification of the Cys(93 beta) residue of Hb Cowtown with N-ethylmaleimide causes a decrease in its oxygen affinity, in contrast to the increase in affinity exhibited by N-ethylmaleimide-modified Hb A. Hemoglobins A and Cowtown have remarkably similar oxygen binding properties after this modification and are shown to have K1 and K4 values distinctly different from those of unmodified Hb A. The properties of native and chemically modified forms of Hb Cowtown are indicative of a large contribution of the His HC3 (146) beta residue to the alkaline Bohr effect and also illustrate how chemical modifications or changes of strategic amino acid residues can result in pronounced differences in the conformational equilibrium of an allosteric protein.

Ethylmaleimide↗
PubMed1976

Screening for abnormal hemoglobins in the middle east: new data on hemoglobin S and the presence of hemoglobin C in Saudi Arabia.

48 of 391 apparently healthy adult Saudi males had an AS hemoglobin pattern on electrophoresis, four subjects had an S pattern, and two subjects AC. A dithionite screening test lacked sensitivity and specificity in detecting hemoglobin S under the conditions of this study. A sickle cell trait frequency of 0.123 evidenced by hemoglobin electrophoresis correlates closely with previous studies of hemoglobinopathies in Saudi Arabs. The presence of four subjects with sickle cell disease in the study group provides further evidence of the "benign" nature of sickle cell disease in Saudi Arabia.

Adolescent↗
PubMed1989

Is hemoglobin a catalyst for sulfoxidation of chlorpromazine? An investigation with isolated purified hemoglobin and hemoglobin in monooxygenase and peroxidase mimicking systems.

The possible role of hemoglobin in the sulfoxidation of chlorpromazine is still a controversial subject. Therefore this sulfoxidation was investigated with purified oxyhemoglobin and methemoglobin under various conditions: (i) in phosphate buffer pH 6.5; (ii) in monooxygenase mimicking systems with electron donors like ascorbic acid and NADPH, the last, with and without an electron carrier like methylene blue and cytochrome c reductase; (iii) in the presence of H2O2. Only in the presence of H2O2 chlorpromazine was converted into chlorpromazine sulfoxide in a considerable amount. This so-called peroxidase activity of hemoglobin appeared not to be based on a Fenton-type reaction. An oxidized reactive form of hemoglobin (i.e. ferrylhemoglobin) is responsible for the sulfoxidation. In the other systems only with ascorbic acid some chlorpromazine sulfoxide was produced. This is probably due to the production of H2O2 and the subsequent peroxidase activity of hemoglobin. Chlorpromazine enhanced the autoxidation of oxyhemoglobin, without being transformed itself.

Chlorpromazine↗
PubMed1991

Preparation, properties, and plasma retention of human hemoglobin derivatives: comparison of uncrosslinked carboxymethylated hemoglobin with crosslinked tetrameric hemoglobin.

Human hemoglobin A has been crosslinked by diisothiocyanatobenzenesulfonate to give a limited number of products in a yield of approximately 70%. The predominant product was crosslinked between subunits within a tetramer and had a Mr of 64,000; no higher Mr species were formed. This product had one crosslink per tetramer located between the NH2 termini of its alpha chains, as established by HPLC analysis, amino acid analysis, Edman degradation, and mass spectrometry. This crosslinked derivative had a slightly increased oxygen affinity [P50 = 9 mmHg (1 mmHg = 133 Pa); P50 for unmodified hemoglobin = 11 mmHg], and the retention time of this derivative in the circulation of rats was 2.9 and 3.3 hr at two hemoglobin concentrations (7 g/dl and 14 g/dl, respectively). The half-life of an uncrosslinked carboxymethylated derivative, which has a low oxygen affinity (P50 = 28 mmHg), was 0.6 and 0.7 hr under the same conditions. Therefore, prolongation of the plasma-retention time of infused hemoglobin is dependent on the crosslinking of the tetramer but independent of the oxygen affinity of the derivative.

Allosteric Regulation↗
PubMed1975

A double heterozygous hemoglobin. Hemoglobin OIndonesia and hemoglobin DPunjab in an individual.

During surveys for abnormal hemoglobins in Iran, an individual was found to have four electrophoretically distinct hemoglobins. The abnormality was found only in the father of the propositus, in two of the father's sisters, and in three brothers and sisters of the propositus. Investigations revealed that the four hemoglobin components are the result of a double heterozygosity between an alpha-chain variant (Hb OIndonesia) and a beta-chain variant (Hb DPunjab). The presence of the abnormal hemoglobins was not associated with hemolytic disorders or obvious clinical symptoms.

Blood Protein Electrophoresis↗
PubMed1975

Two new hemoglobins. Hemoglobin Alabama (beta39(C5)Gln leads to Lys) and hemoglobin Montgomery (alpha 48(CD 6) Leu leads to Arg).

The amino acid substitutions in two new hemoglobins found by electrophoretic screening during a survey in Alabama have been determined by column chromatography and amino acid analyses of their tryptic peptides. They are hemoglobin Alabama (beta 39(C 5)Gln leads to Lys) and hemoglobin Montgomery (alpha 48(CD 6) Leu leads to Arg). No harmful symptoms have been attributed to the presence of either hemoglobin.

Adult↗
PubMed1980

Aggregation of hemoglobin S and hemoglobin CHarlem with nonsickle hemoglobin in concentrated phosphate buffer.

The effect of HbA and HbF on both the aggregation and deaggregation of deoxy HbS and deoxy HbCHarlem in concentrated phosphate buffers was studied by a turbidimetric method. Although pure deoxy HbA is fully soluble in 2.4 M potassium phosphate buffer, the same concentration of deoxy HbAS was insoluble in the same buffer. Since there was little dissolved hemoglobin in the solute of a mixture of HbA and HbS, and since the intensity of turbidity was approximately twice that which would be expected from deoxy HbS alone, deoxy HbA must have coaggregated with deoxy HbS. Similar studies with mixtures of HbS and HbF showed different results. The rates of aggregation of deoxygenated mixtures of HbS and HbF were much slower than those of similar mixtures of HbS and HbA. Measurements of the absorption spectrum of the solute after centrifugation and the electrophoresis of both the aggregates and the solutes showed that a portion of the HbF was coaggregated with HbS, while some of the HbS was still in solution. The solubility of HbS and mixtures of sickle and nonsickle hemoglobins in 2.2 M phosphate buffer increased in the order of HbS, HbACHarlem, HbAS, HbCHarlem, HbSF, and HbFCHarlem.

Blood Protein Electrophoresis↗