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At least 91 records · Page 5Linked to original sources
PubMed1998

Low pulse oximeter-measured hemoglobin oxygen saturations with hemoglobin Cheverly.

Unexpectedly low hemoglobin oxygen saturation as determined by pulse-oximeter analysis was observed in a patient who underwent an elective surgical procedure. Specific hemoglobin derivatives such as carboxyhemoglobin, methemoglobin, and reduced hemoglobin that have been described to lower pulse-oximetry determination of oxygenation were not detected. Absorbance spectra revealed the patient's hemoglobin to be different than that obtained from two normal volunteers. High-pressure liquid chromatographic analysis of the hemoglobin showed an unknown band that comprised 15% of the patient's hemoglobin. DNA sequence analysis showed a point mutation in the second nucleotide of the 45th codon of the beta-globin chain. This mutation encodes for an abnormal beta-chain (beta-45 Phe-->Ser) that has been described as hemoglobin Cheverly. Hemoglobin Cheverly is an unstable hemoglobin that has a similar mutation as the beta-42 Phe-->Ser mutation seen in hemoglobin Hammersmith. Hemoglobin Hammersmith and another unstable hemoglobin, hemoglobin Köln, have previously been described to have unexpectedly low pulse-oximeter-determined oxyhemoglobin levels. That we find hemoglobin Cheverly to result in a similar phenomenon suggests that pulse-oximeter monitoring of oxygenation status may not be appropriate for the unstable hemoglobins. Low pulse-oximeter oxygenation determinations for these hemoglobins do not appear to predict clinical hypoxemia.

Adult↗
PubMed2001

The crystal structure of bar-headed goose hemoglobin in deoxy form: the allosteric mechanism of a hemoglobin species with high oxygen affinity.

The crystal structure of a high oxygen affinity species of hemoglobin, bar-headed goose hemoglobin in deoxy form, has been determined to a resolution of 2.8 A. The R and R(free) factor of the model are 0.197 and 0.243, respectively. The structure reported here is a special deoxy state of hemoglobin and indicates the differences in allosteric mechanisms between the goose and human hemoglobins. The quaternary structure of the goose deoxy hemoglobin shows obvious differences from that of human deoxy hemoglobin. The rotation angle of one alphabeta dimer relative to its partner in a tetramer molecule from the goose oxy to deoxy hemoglobin is only 4.6 degrees, and the translation is only 0.3 A, which are much smaller than those in human hemoglobin. In the alpha(1)beta(2) switch region of the goose deoxy hemoglobin, the imidazole ring of His beta(2)97 does not span the side-chain of Thr alpha(1)41 relative to the oxy hemoglobin as in human hemoglobin. And the tertiary structure changes of heme pocket and FG corner are also smaller than that in human hemoglobin. A unique mutation among avian and mammalian Hbs of alpha119 from proline to alanine at the alpha(1)beta(1 )interface in bar-headed goose hemoglobin brings a gap between Ala alpha119 and Leu beta55, the minimum distance between the two residues is 4.66 A. At the entrance to the central cavity around the molecular dyad, some residues of two beta chains form a positively charged groove where the inositol pentaphosphate binds to the hemoglobin. The His beta146 is at the inositol pentaphosphate binding site and the salt-bridge between His beta146 and Asp beta94 does not exist in the deoxy hemoglobin, which brings the weak chloride-independent Bohr effect to bar-headed goose hemoglobin.

Adaptation, Physiological↗
PubMed1980

Interaction of thyroid hormone and hemoglobin. I. Nature of the interaction and effect of hemoglobin on thyroid hormone radioimmunoassay.

Gel filtration of human RBC lysate incubated with labeled T4 or T3 revealed co-elution of a major iodothyronine-binding fraction (R-2) and hemoglobin. Solutions of purified human hemoglobin and T3 also showed co-elution of hormone and hemoglobin. Because hematin and protoporphyrin were shown to bind labeled T3, the oxygen-binding site on hemoglobin was excluded as the site of iodothyronine-hemoglobin interaction. Analysis of hormone binding by heme and globin moieties showed T3 binding to be limited to the heme fraction. Addition of excess unlabeled T3 to hemoglobin or heme incubated with labeled T3 indicated 75% to 90% of hormone binding was poorly dissociable. These observations suggested that the presence of hemoglobin in RBC lysate or in serum could influence the measurement of T4 and T3 by specific RIA. Subsequent studies of the addition to serum of human hemoglobin revealed a significant reduction in T3 and T4 detectable by RIA in the presence of this protein. The effect was influenced by the concentration of hemoglobin and by duration and temperature of incubations of hemoglobin and serum prior to RIA. Incubated for 5 days at 4 degrees C, 14 sera containing 10 gm/dl hemoglobin showed a mean decrease in T3 concentration of 40% compared to sera incubated in the absence of hemoglobin (160.1 to 93.9 ng/dl, p less than 0.001); detectable serum T4 fell by 50% in 13 sera incubated under the same conditions (5.40 micrograms/dl without hemoglobin to 2.55 micrograms/dl in the presence of hemoglobin, p less than 0.001). Hemoglobin concentrations in serum as low as 0.1 and 0.5 gm/dl affected the RIAs significantly. Thus a major fraction of thyroid hormone binding in human RBC cytoplasm is accounted for by an interaction with hemoglobin. This interaction in serum or RBC lysates is a significant variable affecting iodothyronine determinations.

Anilino Naphthalenesulfonates↗
PubMed1995

Activation of complement by human hemoglobin and by mixtures of hemoglobin and bacterial endotoxin.

Purified human hemoglobin is being developed as an alternative to transfusions of homologous erythrocytes. However, toxicity associated with infusion of hemoglobin has limited the development of this resuscitation fluid. Some observed toxicities, including activation of the complement cascade, have been associated with contamination of hemoglobin solutions by bacterial endotoxin. Recent studies have demonstrated complex formation between hemoglobin and endotoxin, and have documented a resultant increase in the ability of endotoxin to activate coagulation, stimulate tissue factor production by human peripheral blood mononuclear cells, and stimulate tissue factor activity and protein synthesis in cultured human endothelial cells. The process of hemoglobin enhancement of endotoxin toxicity suggests a possible mechanism by which the consequences of endotoxin contamination of hemoglobin solutions, including complement activation, could be magnified. Therefore, we studied the potential of hemoglobin to either fix complement directly, or modify the ability of endotoxin to fix complement. Human crosslinked and native hemoglobins, at concentrations between 0.2 mg/ml and 3 mg/ml, were shown to fix complement. Complement fixation by hemoglobin was identical in normal human serum or in factor B-depleted serum, suggesting that fixation occurred via the classical pathway of complement activation. Complement fixation then was examined with a battery of smooth and rough endotoxins tested in the absence and presence of hemoglobin. Addition of hemoglobin to a solution of a rough Salmonella endotoxin partial structure, from which a single fatty acid had been hydrolyzed from the lipid A portion of the macromolecule, resulted in decreased efficiency of complement fixation. However, addition of hemoglobin had little or no effect on the intrinsic complement fixing abilities of eight other smooth endotoxins, rough endotoxins, or endotoxin partial structures. Our results demonstrated the ability of hemoglobin to fix complement at hemoglobin concentrations which would be achieved during infusion for resuscitation, but failed to demonstrate a reproducible effect of hemoglobin on the activation of complement by endotoxin.

Bacterial Toxins↗
PubMed1998

Modified hemoglobin-based blood substitutes: crosslinked, recombinant and encapsulated hemoglobin.

Native hemoglobin in the form of stroma-free hemoglobin cannot be used as blood substitute. Hemoglobin has to be modified either molecularly or encapsulated. First generation molecularly modified ultrapure hemoglobins are now in clinical trial--some in Phase III. There are a number of these. Polyhemoglobin is formed by crosslinking hemoglobin molecules intermolecularly and intramolecularly. A crosslinked single hemoglobin molecule is formed by crosslinking hemoglobin intramolecularly. Recombinant hemoglobin from E.coli is formed by fusion of the subunits of each hemoglobin molecule. Conjugated hemoglobin is formed by crosslinking each hemoglobin molecule to soluble polymers. A second generation system formed by crosslinking hemoglobin-superoxide dismutase-catalase is being developed. A third generation hemoglobin-based blood substitute is based on microencapsulated hemoglobin, artificial red blood cells, that more closely resemble a complete red blood cell.

Animals↗
PubMed1994

A convenient method for the determination of the solubility of hemoglobin and modified hemoglobins.

The removal of a single charged group can drastically alter the solubility of hemoglobin. Alterations in hemoglobin structure to make it of potential use as a blood substitute must produce derivatives which are sufficiently soluble to allow adequate oxygen delivery. We have developed a convenient method for examining modified hemoglobins. How the polymerization of Hemoglobin S is perturbed in the presence of modified hemoglobins is determined. To measure Hemoglobin S polymerization, a rapid temperature jump from 0 degree and a nitrogen atmosphere [1] are not required. In pH 7.4 phosphate buffers at concentrations greater than 2M containing sodium dithionite, dilute solutions (less than 1 mg/ml) of hemoglobin S aggregate at 30 degrees, or higher, after a delay time (minutes) which depends on the hemoglobin concentration. Light scattering can be used to quantify the extent of polymerization. Chemical modifications of Hemoglobin A can result in altered perturbation of Hemoglobin S polymerization as determined by this method. Modification of hemoglobin to provide suitable oxygen binding characteristics and crosslinking of subunits is a required preliminary to use of hemoglobin as an acellular blood substitute. These modifications often involve the elimination of charged groups from hemoglobin. Information on whether such modifications may have undesirable consequences with respect to solubility properties can be examined using the method described.

Binding Sites↗
PubMed1970

Hemoglobin stability: observations on the denaturation of normal and abnormal hemoglobins by oxidant dyes, heat, and alkali.

Several unstable mutant hemoglobins have alterations which affect areas of the molecule involved in the attachment of heme to globin. Loss of heme from globin has been demonstrated during the denaturation of some of these unstable mutants. The importance of heme ligands for the stability of hemoglobin was illustrated in the present experiments on the denaturation of several hemoglobins and hemoglobin derivatives by heat, oxidative dyes, and alkali. Heating of normal hemolysates diluted to 4 g of hemoglobin per 100 ml at 50 degrees C for 20 hr in 0.05 M sodium phosphate, pH 7.4, caused precipitation of 23-54% of the hemoglobin. Dialysis against water or dilution of the sample decreased denaturation to 12-20%. Precipitation was decreased to less than 3.5% by the presence of 0.015 M potassium cyanide. Increasing the ionic strength of the medium increased precipitation. Cyanide prevented the formation of inclusion bodies when red cells containing unstable hemoglobin Philly, beta35 tyr --> phe, were incubated with the redox dye new methylene blue. Conversion to methemoglobin increased the rate of alkali denaturation of hemoglobin but the presence of potassium cyanide returned the denaturation rate to that of ferrohemoglobin. The ability of cyanide to decrease heat precipitation of hemoglobin may depend on a dimeric or tetrameric state of the hemoglobin molecule. Purified beta-chains, which exist as tetramers, were stabilized but purified monomeric alpha-chains were not rendered more heat resistant by the ligand. Stabilization of hemoglobin by cyanide required binding of the ligand to only one heme of an alphabeta-dimer. Hemoglobin Gun Hill, an unstable molecule with heme groups present only on the alpha-chains was quite heat stable in the presence of cyanide. The binding of cyanide to the iron atom in methemoglobin is thought to be associated with increased planarity of the heme group and increased stability of the heme-globin complex. The stabilizing effect of cyanide in the above experiments suggests that Heinz body formation, heat precipitation of hemoglobin, and the increased alkali denaturation of methemoglobin depend on changes of heme-globin binding.

Alkalies↗
PubMed1975

Hemoglobin Syracuse (alpha2beta2-143(H21)His leads to Pro), a new high-affinity variant detected by special electrophoretic methods. Observations on the auto-oxidation of normal and variant hemoglobins.

Family members from four generations were found to have polycythemia and increased whole blood O2 affinity (P50; 11 mm Hg; normal, 27 mm Hg). No abnormal hemoglobin bands were seen after electrophoresis on starch gel at pH 8.6 or agar gel at pH 6.0. Analysis of the oxygenated hemolysate by isoelectric focusing on polyacrylamide gel revealed two closely spaced bands. When deoxygenated hemolysate was analyzed in oxygen-free gels, the two components were more widely separated. About 40% of the patient's hemoglobin focused at a more acid pH than hemoglobin A, indicating a hemoglobin variant with impaired Bohr effect. Chromatography of globin in 8 M urea revealed two beta-chain peaks, the first of which was eluted at a lower buffer molarity than normal beta chain. Fingerprints of tryptic digests of the aminoethylated chains were done on silica gel thin-layer plates. Tp 14 from the abnormal beta chain had slower electrophoretic mobility and a greater Rf value. Amino acid analyses of this peptide gave values identical with those of betaTp 14, except that it contained one proline residue and no histidine. Since the one His in betaTp 14 is in position 143, hemoglobin Syracuse in alpha2beta2-143 His leads to Pro. Native Hb Syracuse could be separated from hemoglobin A on a carboxymethylcellulose column. The inclusion of 0.1 mM EDTA in the preparative buffers proved very useful in reducing the formation of methemoglobin. Oxygen equilibria of purified hemoglobin Syracuse showed high oxygen affinity (P50 value 12% that of hemoglobin A) and lack of cooperativity between subunits (Hill's n equals 1.1). The alkaline Bohr effect was about half that of hemoglobin A. The proline substitution at betaH21 disrupts the helical configuration and probably prevents the formation of salt bonds that are important in stabilizing the deoxy structure and contribute to the alkaline Bohr effect. Since beta143 His is a binding site for 2,3-diphosphoglycerate (2,3-DPG), it is not suprising that hemoglobin Syracuse had markedly impaired reactivity with 2,3-DPG. Hemoglobin Syracuse auto-oxidized more slowly than hemoglobin A, probably reflecting a slower rate of dissociation of oxygen from fully liganded hemoglobin.

Adult↗
PubMed1987

False elevation of hemoglobin A1 by hereditary persistence of fetal hemoglobin.

Measurement of glycosylated hemoglobin (HgA1) is frequently helpful in the management of patients with diabetes mellitus as it provides an index of average glucose control over the previous two to three months. The present case of a diabetic patient with a markedly increased hemoglobin A1 to 42% (normal 5.2-9.2%) with good glucose control prompted an investigation into the etiology of the increased hemoglobin A1 levels. Hemoglobin electrophoresis revealed that the patient had hereditary persistence of fetal hemoglobin. Hemoglobin F was quantitated and found to be responsible for 73% of the hemoglobin A1 determination. Hemoglobin F co-migrates with hemoglobin A1 on column chromatography and, when present in increased quantities, can falsely elevate the measured hemoglobin A1. Thus, if one utilizes the hemoglobin A1 assay to help guide management of patients with diabetes mellitus, it is important to remember that hemoglobin F can cause falsely elevated hemoglobin A1 levels.

Adult↗
PubMed1976

Studies on camel hemoglobin. 1. Physico-chemical properties and some structural aspects of camel hemoglobin (Camelus dromedarius).

Hemoglobin from an adult camel (Camelus dromedarius) was prepared from the red cell lysate by CM- and DEAE-cellulose chromatography. The purified hemoglobin showed a lesser mobility on starch gel electrophoresis at pH 8.5 than that of human hemoglobin C. Native camel hemoglobin contains 95-99% alkali-resistant hemoglobin and in soluble in 2.94 M K2HPO4/KH2PO4 buffer. Different forms of camel hemoglobin show similar ammonium sulfate precipitation curves. Indirect evidence for the stability of camel hemoglobin solutions was obtained from several sources. Spontaneous met-hemoglobin formation is extremely slow and minimal quantities of degradation products appear on starch gel electrophoresis and on chromatographic separation. The alpha and beta chains of camel hemoglobin A were separated on a CM-23 column by the use of a pyridine formate gradient. Large peptide fragments were obtained by tryptic digestion of maleylated alpha and beta chains. The N-terminal structure of the alpha and beta chains and of tryptic maleylated peptides derived from alpha and beta chains are presented. Between adult camel hemoglobin and adult human hemoglobin six amino acid differences in the N-terminal 20 amino acid residues of the alpha chain, at residues: 4, 5, 12, 14, 17, and 19; eight amino acid substitutions were found in the beta chain at positions: 4, 5, 6, 9, 12, 13, 16, and 19. Substitutions at alpha5 Ala leads to Lys, and beta19 Asn leads to Lys, increase the net positive charge of camel hemoglobin by two, while other substitutions result in no charge differences. The molecular basis of the stability of camel adult hemoglobin is discussed.

Amino Acid Sequence↗
PubMed1969

Hemoglobin Philly (beta 35 tyrosine phenylalanine): studies in the molecular pathology of hemoglobin.

An abnormal unstable hemoglobin, hemoglobin Philly, was found in three members of a family, each of whom had evidence of a chronic hemolytic state. The presence of the mutant protein was suggested by the rapid appearance of inclusion bodies upon incubation of erythrocytes with brilliant cresyl blue and by the increased heat precipitability of the hemoglobin. However, no abnormal hemoglobin could be demonstrated by electrophoresis or column chromatography. Sulfhydryl titration of the hemolysates with p-mercuribenzoate indicated that there was an average of four reactive sulfhydryl groups per hemoglobin molecule instead of the usual two. The total number of hemoglobin sulfhydryl groups was normal; six groups were measured when denatured globin was reacted with 5,5'-dithiobis[2-nitrobenzoic acid]. This indicated that the increased sulfhydryl reactivity was due to an increased availability to p-mercuribenzoate of the usually unreactive hemoglobin cysteines at beta112 and alpha104. After treatment for (1/2) hr with 4-5 moles of p-mercuribenzoate per mole of hemoglobin, electrophoresis revealed that 30-35% of the hemoglobin had been dissociated into alpha- and beta-chains. Normal hemolysates revealed negligible splitting after 72 hr of similar treatment. The alpha- and beta-chains of hemoglobin Philly were separated from the unsplit hemoglobin A by carboxymethyl cellulose chromatography. Fingerprint and amino acid analyses revealed that tyrosine beta35 was replaced by phenylalanine. In hemoglobin Philly there is loss of the normal hydrogen bond between the tyrosine hydroxyl group and the carboxyl group of aspartic acid alpha126 at the alpha(1)beta(1) contact. This shifts the equilibrium from hemoglobin tetramers toward monomers, exposing the beta112 and alpha104 cysteines. In the cell, precipitation of the unstable monomers may contribute to erythrocyte destruction.

Amino Acids↗