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At least 19 recordsLinked to original sources
PubMed1984

Alternative diaspirins for modification of hemoglobin and sickle hemoglobin.

Studies of modification of hemoglobin and of sickle hemoglobin by alternative aspirins have been extended to a series of new bis esters with a variety of substituted bridging diacids and to a group of mono esters with polar acyl groups. Rates of hydrolysis of these alternative aspirins have also been examined, and they reveal that a careful balance between stability and reactivity is essential for optimal activity. Four-carbon bridging groups have been found to be particularly effective, two of these raising the minimum gelling concentration of sickle hemoglobin by as much as 100%.

Adult↗
PubMed1997

Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease.

To create mice expressing exclusively human sickle hemoglobin (HbS), transgenic mice expressing human alpha-, gamma-, and betaS-globin were generated and bred with knockout mice that had deletions of the murine alpha- and beta-globin genes. These sickle cell mice have the major features (irreversibly sickled red cells, anemia, multiorgan pathology) found in humans with sickle cell disease and, as such, represent a useful in vivo system to accelerate the development of improved therapies for this common genetic disease.

Anemia, Sickle Cell↗
PubMed1981

Structural specificities in acylation of hemoglobin and sickle hemoglobin by diaspirins.

Double-headed aspirins with bridging groups of different length and molecular structure have been examined for their reactivity with hemoglobin A or S. The compounds constructed are bound in the beta-cleft and show a wide range of beta-beta cross-linking effectiveness. Oxygenation curves of the modified hemoglobins in the presence of inositol hexaphosphate are strikingly modified. Many of the diaspirins also produce substantial changes in the minimum gelling concentration of sickle hemoglobin. These reagents offer possibilities for further enhancement of specificity toward hemoglobin, particularly by taking advantage of stereoselectivities.

Aspirin↗
PubMed2000

The reactions of myoglobin, normal adult hemoglobin, sickle cell hemoglobin and hemin with hydroxyurea.

The kinetics of the reaction of hydroxyurea (HU) with myoglobin (Mb), hemin, sickle cell hemoglobin (HbS), and normal adult hemoglobin (HbA) were determined using optical absorption spectroscopy as a function of time, wavelength, and temperature. Each reaction appeared to follow pseudo-first order kinetics. Electron paramagnetic resonance spectroscopy (EPR) experiments indicated that each reaction produced an FeNO product. Reactions of hemin and the ferric forms of HbA, HbS, and myoglobin with HU also formed the NO adduct. The formation of methemoglobin and nitric oxide-hemoglobin from these reactions may provide further insight into the mechanism of how HU benefits sickle cell patients.

Adult↗
PubMed1995

Contributions of sickle hemoglobin polymer and sickle cell membranes to impaired filterability.

Sickle cell anemia is a disease of abnormal rheology caused by acute and reversible, as well as chronic and irreversible, changes in the properties and deformability of sickle erythrocytes. Deformability is determined by several factors, including intracellular sickle hemoglobin polymerization, the abnormal membrane properties of sickle cells, and the abnormal rheological properties of the soluble concentrated hemoglobin solution within dense sickle red blood cells. In this study, we used a 5-microns pore nickel mesh filter to evaluate quantitatively the effects of these factors on the filterability of erythrocytes containing sickle hemoglobin. We used sickle trait and sickle/beta(+)-thalassemia cells, because they have minimal membrane abnormalities or density heterogeneity, to investigate the effects of polymer formation on rheological properties. We found that filterability of these cells is sensitive to small amounts of intracellular polymer and that impaired filtration is linearly related to oxygen-dependent polymer formation, up to a polymer fraction of 0.3. By increasing the proportion of dense cells in populations of normal cells or cells from individuals with sickle syndromes and equilibrating these cells with gas ligands, we estimate that polymerization, even at 95% saturation, contributes twice as much to impaired filterability of sickle erythrocytes as the abnormal membranes in homozygous sickle cell disease. At lower saturation values, the effects of polymer are even greater. The viscosity of the concentrated hemoglobin in dense cells had the smallest effect, over physiologically relevant saturation values. These results emphasize the importance of sickle hemoglobin polymerization in the pathogenesis of sickle cell disease and should help define its pathophysiology and responses to therapy in quantitative terms.

Anemia, Sickle Cell↗
PubMed1995

Bacteremia in children with sickle hemoglobin C disease and sickle beta(+)-thalassemia: is prophylactic penicillin necessary?

OBJECTIVE: To characterize the incidence of bacteremia and its potential for progression to septicemia in children with sickle hemoglobin C disease and sickle beta(+)-thalassemia to assess the need for penicillin prophylaxis. STUDY DESIGN: Retrospective chart review of the frequency and natural history of bloodstream infection in such patients not receiving prophylactic penicillin therapy and followed up in a single institution. RESULTS: During more than 842 patient-years of observation in 242 patients with sickle hemoglobin C disease, 15 episodes of bacteremia occurred in nine patients. Septicemia was fatal in one patient. The overall incidence of bacteremia, 1.8 events per 100 patient-years (95% confidence limits: 0.8, 2.8) in patients with sickle hemoglobin C disease, was similar to that in hematologically normal children. One episode of bacteremia occurred in a patient with sickle beta(+)-thalassemia. CONCLUSIONS: The incidence of bacteremia is not increased in young patients with sickle hemoglobin C disease and sickle beta(+)-thalassemia. Further, unlike its course in children with sickle cell anemia, it rarely evolves into life-threatening septicemia. This probably results from the maintenance of relatively intact splenic function during infancy and early childhood in patients with sickle hemoglobin C disease and sickle beta(+)-thalassemia. Prophylactic penicillin therapy may not be required in these patients.

Adolescent↗
PubMed1996

A 50th order reaction predicted and observed for sickle hemoglobin nucleation.

Sickle hemoglobin polymerization exhibits a striking sensitivity to initial concentration, with characteristic reaction times that exhibit 30th power dependence on concentration. This extraordinary reaction order is encompassed by a novel double nucleation mechanism that predicts 50th power dependence of the homogeneous nucleation rate. Using a technique that allows individual homogeneous nucleation events to be monitored, we have measured a concentration dependence of 47+/-, in excellent agreement with the predictions of the model. Absolute nucleation rates agree with predictions as well.

Biopolymers↗
PubMed1977

Hemoglobin S Travis: a sickling hemoglobin with two amino acid substitutions [beta6(A3)glutamic acid leads to valine and beta142 (h20) alanine leads to valine).

Hb S Travis is a previously undescribed sickling hemoglobin with two amino acid substitutions in the beta chain: beta6 Glu leads to Val and beta142 Ala leads to Val. The beta6 Glu leads to Val mutation imparts to Hb S Travis the characteristic properties of sickling hemoglobin, namely its association with erythrocyte sickling, the insolubility of the hemoglobin in the reduced form, and a minimum gelling concentration value identical to Hb S. Unlike Hb S, Hb S Travis exhibits an increased oxygen affinity and a decreased affinity for 2,3-bisphosphoglycerate and inositol hexakisphosphate. In addition, the variant hemoglobin's tendency to autoxidize and its mechanical precipitability suggest that there are conformational differences between Hb S and Hb S Travis.

Alanine↗
PubMed1988

Structural analysis of polymers of sickle cell hemoglobin. II. Sickle hemoglobin macrofibers.

Sickle cell hemoglobin macrofibers are an important intermediate in the low pH crystallization pathway of deoxygenated hemoglobin S that link the fiber to the crystal. Macrofibers are a class of helical particles differing primarily in their diameters but are related by a common packing of their constituent subunits. We have performed three-dimensional reconstructions of three types of macrofibers. These reconstructions show that macrofibers are composed of rows of Wishner-Love double strands in an arrangement similar to that in the crystal. We have measured the orientation and co-ordinates of double strands in macrofibers using cross-correlation techniques. In this approach, the electron density projections of double strands calculated from the known high-resolution crystal structure are compared with regions along the length of the particles in which the distinct pattern of double strands in c-axis projection may be observed. Contrary to assertions by Makinen & Sigountos (1984), our results unambigously demonstrate that adjacent rows of double strands in macrofibers are oriented in an antiparallel manner, as in the Wishner-Love crystal. Adjacent rows of antiparallel double strands are displaced along the helical axis relative to their co-ordinates in the crystal. Electron density models of macrofibers based on the crystallographic structure of the sickle hemoglobin double strand are in good agreement with the projections of macrofibers observed in electron micrographs. We have studied the structure of a closely related crystallization intermediate, the sickle hemoglobin paracrystal. The arrangement of double strands in paracrystals is similar to that in Wishner-Love crystals, except that they are displaced along the a-axis of the crystal. Measurements of the double strand co-ordinates reveal that the distribution of strand positions is bimodal. These results further establish the close structural relationship between macrofibers and paracrystals as intermediates in the crystallization of deoxygenated sickle hemoglobin.

Computer Simulation↗
PubMed2005

The effects of erythrocyte membranes on the nucleation of sickle hemoglobin.

Pathology in sickle cell disease begins with nucleation-dependent polymerization of deoxyhemoglobin S into stiff, rodlike fibers that deform and rigidify red cells. We have measured the effect of erythrocyte membranes on the rate of homogeneous nucleation in sickle hemoglobin, using preparations of open ghosts (OGs) with intact cytoskeletons from sickle (SS) and normal adult (AA) red cells. Nucleation rates were measured by inducing polymerization by laser photolysis of carboxy sickle hemoglobin and observing stochastic variation of replicate experiments of the time for the scattering signals to reach 10% of their respective maxima. By optical imaging of membrane fragments added to a hemoglobin solution we contrast the rate of nucleation immediately adjacent to membrane fragments with nucleation in a region of the same solution but devoid of membranes. From analysis of 29,272 kinetic curves obtained, we conclude that the effect of AA OGs is negligible (10% enhancement of nucleation rates +/-20%), whereas SS OGs caused 80% enhancement (+/-20%). In red cells, where more membrane surface is available to Hb, this implies enhancement of nucleation by a factor of 6. These experiments represent a 10-fold improvement in precision over previous approaches and are the first direct, quantitative measure of the impact of erythrocyte membranes on the homogeneous nucleation process that is responsible for polymer initiation in sickle cell disease.

Anemia, Sickle Cell↗
PubMed2000

Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review.

Sickle cell disease is caused by a variant of the beta-globin gene called sickle hemoglobin (Hb S). Inherited autosomal recessively, either two copies of Hb S or one copy of Hb S plus another beta-globin variant (such as Hb C) are required for disease expression. Hb S carriers are protected from malaria infection, and this protection probably led to the high frequency of Hb S in individuals of African and Mediterranean ancestry. Despite this advantage, individuals with sickle cell disease exhibit significant morbidity and mortality. Symptoms include chronic anemia, acute chest syndrome, stroke, splenic and renal dysfunction, pain crises, and susceptibility to bacterial infections. Pediatric mortality is primarily due to bacterial infection and stroke. In adults, specific causes of mortality are more varied, but individuals with more symptomatic disease may exhibit early mortality. Disease expression is variable and is modified by several factors, the most influential being genotype. Other factors include beta-globin cluster haplotypes, alpha-globin gene number, and fetal hemoglobin expression. In recent years, newborn screening, better medical care, parent education, and penicillin prophylaxis have successfully reduced morbidity and mortality due to Hb S.

Adolescent↗
PubMed1994

Properties of a recombinant human hemoglobin double mutant: sickle hemoglobin with Leu-88(beta) at the primary aggregation site substituted by Ala.

A recombinant double mutant of hemoglobin (Hb), E6V/L88A(beta), was constructed to study the strength of the primary hydrophobic interaction in the gelation of sickle Hb, i.e., that between the mutant Val-6(beta) of one tetramer and the hydrophobic region between Phe-85(beta) and Leu-88(beta) on an adjacent tetramer. Thus, a construct encoding the donor Val-6(beta) of the expressed recombinant HbS and a second mutation encoding an Ala in place of Leu-88(beta) was assembled. The doubly mutated beta-globin gene was expressed in yeast together with the normal human alpha-chain, which is on the same plasmid, to produce a soluble Hb tetramer. Characterizations of the Hb double mutant by mass spectrometry, by HPLC, and by peptide mapping of tryptic digests of the mutant beta-chain were consistent with the desired mutations. The absorption spectra in the visible and the ultraviolet regions were practically superimposable for the recombinant Hb and the natural Hb purified from human red cells. Circular dichroism studies on the overall structure of the recombinant Hb double mutant and the recombinant single mutant, HbS, showed that both were correctly folded. Functional studies on the recombinant double mutant indicated that it was fully cooperative. However, its gelation concentration was significantly higher than that of either recombinant or natural sickle Hb, indicating that the strength of the interaction in this important donor-acceptor region in sickle Hb was considerably reduced even with such a conservative hydrophobic mutation.

Alanine↗
PubMed1987

Membrane-associated sickle hemoglobin: a major determinant of sickle erythrocyte rigidity.

Micropipette aspiration tests on single erythrocytes have previously shown that the static rigidity (membrane shear modulus) of oxygenated sickle cells increased with increasing hemoglobin concentration, whereas the rigidity of normal cells was independent of hemoglobin concentration. Moreover, it was observed that after mechanical extension, sickle cells exhibited persistent deformation more frequently and to a greater extent than normal cells. To ascertain if differences in association of normal and sickle hemoglobin with the membrane could account for these observations, we measured rheologic properties of normal membranes reconstituted with sickle hemoglobin and sickle membranes reconstituted with normal hemoglobin. The static rigidity of normal ghosts reloaded with sickle hemoglobin was higher than those of either normal ghosts reloaded with normal hemoglobin or native normal cells. On the other hand, the increased rigidity of native sickle cells decreased to near-normal values following reconstitution with normal hemoglobin. Furthermore, we observed that normal ghosts reconstituted with sickle hemoglobin exhibited persistent bumps after mechanical extension, but no bumps formed on normal ghosts reconstituted with normal hemoglobin. Moreover residual bumps were not produced on sickle cells reloaded with normal hemoglobin. Since mechanical characteristics peculiar to sickle cells could be induced in normal cells by incorporation of sickle hemoglobin, and since normal characteristics could be restored to sickle cells by incorporation of normal hemoglobin, we suggest that the interaction of sickle hemoglobin with the cell membrane is responsible for augmented static rigidity of oxygenated sickle erythrocytes.

Anemia, Sickle Cell↗
PubMed1993

Recombinant human sickle hemoglobin expressed in yeast.

Sickle hemoglobin has been expressed in the yeast Saccharomyces cerevisiae after site-directed mutagenesis of a plasmid containing normal human alpha- and beta-globin genes. Cassette mutagenesis of this plasmid was achieved by inserting a DNA fragment containing the beta-globin gene in the replicative form of M13mp18 to make a point mutation and then reconstituting the original plasmid containing the mutated beta-globin gene. Pure recombinant hemoglobin S was shown to be identical to natural sickle hemoglobin in its ultraviolet and visible absorption bands and by gel electrophoresis, isoelectric focusing, amino acid analysis, mass spectrometry, partial N-terminal sequencing, and functional properties (P50, cooperativity, and response to 2,3-bisphosphoglycerate). In yeast and in mammalian cells, cotranslational processing yields the same N-terminal valine residues of hemoglobin alpha- and beta-chains, but in bacterial expression systems the N terminus is extended by an additional amino acid because the initiator methionine residue is retained. Since the N-terminal valine residues of both chains of hemoglobin S participate in important physiological functions, such as oxygen affinity, interaction with anions, and the Bohr coefficient, the yeast expression system is preferable to the bacterial system for recombinant DNA studies. Hence, mutagenesis employing this expression system should permit definitive assignments of the role of any amino acid side chain in hemoglobin S aggregation and could suggest additional approaches to therapeutic intervention. The engineering of this system for the synthesis of sickle hemoglobin and its purification to homogeneity in a single column procedure are described.

Amino Acid Sequence↗
PubMed2002

Heterogeneous nucleation and crowding in sickle hemoglobin: an analytic approach.

Sickle hemoglobin nucleation occurs in solution as a homogeneous process or on existing polymers in a heterogeneous process. We have developed an analytic formulation to describe the solution crowding and large nonideality that affects the heterogeneous nucleation of sickle hemoglobin by using convex particle theory. The formulation successfully fits the concentration and temperature dependence of the heterogeneous nucleation process over 14 orders of magnitude. Unlike previous approaches, however, the new formulation can also accurately describe the effects of adding nonpolymerizing agents to the solution. Without additional adjustable parameters, the model now describes the data of M. Ivanova, R. Jasuja, S. Kwong, R. W. Briehl, and F. A. Ferrone, (Biophys. J. 2000, 79:1016-1022), in which up to 50% of the sickle hemoglobin is substituted by cross-linked hemoglobin A, which does not polymerize, and which substitution causes the rates to decrease by 10(5). The success of this approach provides insight into the polymerization process: from the size-dependence of the contact energy deduced here, it also appears that various contacts of unknown origin are energetically significant in the heterogeneous nucleation process.

Calorimetry↗