Oxygen Equilibrium Characteristics of Abnormal Hemoglobins: Hirose (α2β237Ser), L Ferrara (α247Glyβ2), Broussais (α290Asnβ2), and Dhofar (α2β258Arg)

Fujita, Shigeru

doi:10.1172/jci107067

Cited by 16 publications

(5 citation statements)

References 32 publications

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“…Effects of substitution at the βW37 position on O 2 binding properties has been previously characterized for a number of other recombinant and naturally occurring mutant Hbs. Recombinant Hbs βW37F and βW37T, and the naturally occurring mutant Hbs Howick (βW37G) and Hirose (βW37S) were found, as the mutants of this study, to have increased binding affinity and decreased cooperativity (Brittain, 1994;Fujita, 1972;Ishimori et al, 1992;Owen et al, 1993;Yamaoka, 1971). These effects, however, were attributed mainly to enhanced tetramer to dimer dissociation in which the dimers and tetramers were assumed to bind O 2 with wildtype affinities.…”

Section: Discussionmentioning

confidence: 52%

Thermodynamic Studies on the Equilibrium Properties of a Series of Recombinant βW37 Hemoglobin Mutants

et al. 1998

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In human hemoglobin (Hb) the beta37 tryptophan residue (betaW37), located at the hinge region of the alpha1beta2 interface, forms many contacts with alpha subunit residues of the opposite dimer, in both the T and R quaternary structures. We have carried out equilibrium O2 binding studies on a series of recombinant Hbs that have mutations at this residue site: betaW37Y, betaW37A, betaW37G, and betaW37E. Binding isotherms measured at high concentrations of these mutants were found to be shifted toward increased affinity and decreased cooperativity from that of the normal HbA0 tetramer. Analysis of these binding isotherms indicated that amino acid substitutions at the beta37 position could both destabilize the tetrameric form of the mutants relative to their constituent dimers and also alter cooperativity of the intact tetrameric species. These alterations from wild-type function are dependent on the particular side chain substituted, with the magnitude of change increasing as Trp is substituted by Tyr, Ala, Gly, and Glu. The dimer to tetramer assembly free energy of deoxy-betaW37E, the most perturbed mutant in the series, was measured using analytical gel chromatography to be 9 kcal/tetramer less favorable than that of deoxy HbA0. Stabilizing the betaW37E tetramer by addition of IHP, or by cross-linking at the alphaK99 positions, does not restore normal O2 binding behavior. Thermodynamic parameters of all the mutants were found to correlate with their CO binding rates and with their high-resolution X-ray crystal structures (see accompanying papers: Kwiatkowski et al. (1998) Biochemistry 37, 4325-4335; Peterson & Friedman (1998) Biochemistry 37, 4346-4357; Kavanaugh et al. (1998) Biochemistry 37, 4358-4373].

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Section: Discussionmentioning

confidence: 52%

Thermodynamic Studies on the Equilibrium Properties of a Series of Recombinant βW37 Hemoglobin Mutants

et al. 1998

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“…Based on these considerations we think that it is justified to say that our hydrogen ion titration data strongly suggest that His-89a (FGl), which is masked in hemoglobin, becomes titratable in des-Arg14'"hemoglobin and that either Lys-9Oa (FG2) or Arg-92a (FG4) becomes masked in dk~-Arg'~'"-hemoglobin. The high oxygen affinity of des-ArgI4' "-hemoglobin and the low cooperativity of its ligand binding [4-61 is in accordance with this interpretation, since mutant hemoglobins with an amino acid replacement in the FG region, like the hemoglobins Capetown ( [ G~I I~~" ]hemoglobin), Cheseapeake ([Le~~~"]hemoglobin) and Malmo ( [Gln97B]hemoglobin) [35,36], show similar abnormal ligand-binding behaviour.…”

Section: Discussionmentioning

confidence: 86%

The Binding of Protons and Inositol Hexakisphosphate to Ligated and Unligated Human Des‐Arg^141α‐hemoglobin

Beek

Zuiderweg

Bruin

1978

European Journal of Biochemistry

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Des‐Arg‐141α‐hemoglobin has been prepared and its proton binding behaviour has been studied. It appeared that the difference in protons bound by hemoglobin and des‐Arg141α‐hemoglobin cannot be explained by the mere absence of Arg‐141α. The results indicate that upon removal of Arg‐141α, two lysyl or arginyl residues become masked and two histidyl residues titratable. The Bohr effect of des‐Arg141α‐hemoglobin appear to be lower than that of hemoglobin. We present evidence that this phenomenon is for the greater part due to the absence of a pK shift of Val‐1α upon ligation of des‐Arg141α‐hemoglobin. This follows from a study of the pH‐dependence of the rate of reaction of 1‐fluoro‐2,4‐dinitro‐benzene with the amino group of Val‐1α. In the presence of inositol hexakisphosphate the Bohr effect of des‐Arg141α‐hemoglobin is still smaller than that of hemoglobin in the presence of this polyanion. Above pH 7 the proton uptake by des‐Arg141α‐hemoglobin upon binding of inositol hexakisphosphate is smaller than that observed for hemoglobin. The possibility is discussed that the change in proton binding behaviour of hemoglobin upon removal of Arg‐141α is due to a conformational change in the FG region of the α chains. As a result His‐89α becomes titratable and Lys‐90α or Arg‐92α masked. This change in conformation might also be the reason for the high oxygen affinity and the low cooperativity of des‐Arg141α‐hemoglobin.

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“…rs33991059 has Tryptophan being substituted by Ser at position 38. Experimental studies that have confirmed the existence of this mutation include but are not limited to the researches of Fujita [51], Yamaoka [52], Kornblit et al [53] etc. Arginine is substituted by Glycine at position 31 of the beta subunit of HBB [54].…”

Section: Discussionmentioning

confidence: 99%

Computational and drug target analysis of functional single nucleotide polymorphisms associated with Haemoglobin Subunit Beta (HBB) gene

Soremekun

Ezenwa

Isewon

et al. 2020

Computers in Biology and Medicine

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There is overwhelming evidence implicating Haemoglobin Subunit Beta (HBB) protein in the onset of beta thalassaemia. In this study for the first time, we used a combined SNP informatics and computer algorithms such as Neural network, Bayesian network, and Support Vector Machine to identify deleterious non-synonymous Single Nucleotide Polymorphisms (nsSNPs) present in the HBB gene. Our findings highlight three major mutation points (R31G, W38S, and Q128P) within the HBB gene sequence that have significant statistical and computational associations with the onset of beta thalassaemia. The dynamic simulation study revealed that R31G, W38S, and Q128P elicited high structural perturbation and instability, however, the wild type protein was considerably stable. Ten compounds with therapeutic potential against HBB were also predicted by structure-based virtual screening. Interestingly, the instability caused by the mutations was reversed upon binding to a ligand. This study has been able to predict potential deleterious mutants that can be further explored in the understanding of the pathological basis of beta thalassaemia and the design of tailored inhibitors.

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Oxygen Equilibrium Characteristics of Abnormal Hemoglobins: Hirose (α2β237Ser), L Ferrara (α247Glyβ2), Broussais (α290Asnβ2), and Dhofar (α2β258Arg)

Cited by 16 publications

References 32 publications

Thermodynamic Studies on the Equilibrium Properties of a Series of Recombinant βW37 Hemoglobin Mutants

Thermodynamic Studies on the Equilibrium Properties of a Series of Recombinant βW37 Hemoglobin Mutants

The Binding of Protons and Inositol Hexakisphosphate to Ligated and Unligated Human Des‐Arg^141α‐hemoglobin

Computational and drug target analysis of functional single nucleotide polymorphisms associated with Haemoglobin Subunit Beta (HBB) gene

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Oxygen Equilibrium Characteristics of Abnormal Hemoglobins: Hirose (α2β237Ser), L Ferrara (α247Glyβ2), Broussais (α290Asnβ2), and Dhofar (α2β258Arg)

Cited by 16 publications

References 32 publications

Thermodynamic Studies on the Equilibrium Properties of a Series of Recombinant βW37 Hemoglobin Mutants

Thermodynamic Studies on the Equilibrium Properties of a Series of Recombinant βW37 Hemoglobin Mutants

The Binding of Protons and Inositol Hexakisphosphate to Ligated and Unligated Human Des‐Arg141α‐hemoglobin

Computational and drug target analysis of functional single nucleotide polymorphisms associated with Haemoglobin Subunit Beta (HBB) gene

Contact Info

Product

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About

The Binding of Protons and Inositol Hexakisphosphate to Ligated and Unligated Human Des‐Arg^141α‐hemoglobin