Hemoglobin providence. Functional consequences of two alterations of the 2,3-diphosphoglycerate binding site at position beta 82.

Bonaventura, Joseph; Bonaventura, Celia; Sullivan, Bolling; Ferruzzi, G; McCurdy, Paul R.; Fox, J. A.; Moo-Penn, Winston F.

doi:10.1016/s0021-9258(17)32888-0

Cited by 115 publications

(41 citation statements)

References 32 publications

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“…The lower oxygen affinity is similar to that of other hemoglobins which are blocked at the N terminus of the polypeptide chain (Bunn et al, 1970). Lower oxygen affinities are also characteristic of some human hemoglobin variants with mutations which result in a reduction of positive charge density at the cofactor binding site (Bonaventura et al, 1974a(Bonaventura et al, ,b, 1976. Reduction in the net positive charge of the DPG binding site by a mutational event could be a factor in decreasing the oxygen affinity through stabilization of the deoxy conformation of the variant hemoglobin.…”

Section: Discussionmentioning

confidence: 53%

“…The eight cationic groups normally involved in the binding of organic phosphates are the Val-1, His-2, Lys-82, and His-143 residues of the 8 chains (Arnone, 1972). Naturally occurring variants involving all of these positions except the 81 Val position have been described (Bare et al, 1974;Bonaventura et al, 1975aBonaventura et al, ,b, 1976Jensen et al, 1975;Lorkin et al, 1975; Moo-Penn et al, 1976). In Hb Raleigh, the substitution of alanine for valine does not lead to a charge change.…”

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confidence: 99%

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Hemoglobin Raleigh (β1 valine →acetylalanine). Structural and functional characterization

Moo-Penn¹,

Bechtel²,

Schmidt³

et al. 1977

Biochemistry

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Section: Discussionmentioning

confidence: 53%

mentioning

confidence: 99%

Hemoglobin Raleigh (β1 valine →acetylalanine). Structural and functional characterization

Moo-Penn¹,

Bechtel²,

Schmidt³

et al. 1977

Biochemistry

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“…A mechanistic interpretation of the effects of different chloride concentrations on the kinetics of CO binding, namely the lack of any observable effect at pH 6.3 and 8.5 and a slight effect at pH 7, would be speculative since the data are not sufficiently precise. A structural interpretation is complicated by the existence of at least two classes of sites for chloride binding, involving the R-amino group of Val1(R) (30,31) and the -amino group of Lys82(β) (32), characterized by different affinities for the ligand and pH dependence of the affinities. However, the findings reported here and in other works, quoted above, that chloride, proton and organic phosphate elicit different, or opposite, effects on ligand binding to the R and β chains suggest the possibility that mechanisms of interaction among the modulators of oxygen affinity exist, which could be of significance for the fine-tuning of oxygen delivery to the tissues.…”

Section: Schemes Of Multiple Pathways Of Reactionmentioning

confidence: 99%

Modulation of the Association Reaction between Hemoglobin and Carbon Monoxide by Proton and Chloride

1998

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A cryogenic technique for the isolation of the ligation intermediates in the association reaction between hemoglobin and carbon monoxide at 20 degrees C [Perrella, M., Davids, N., and Rossi-Bernardi, L. (1992) J. Biol. Chem. 267, 8744-8751] was used to study the effects of proton and chloride concentrations on the rates of the stepwise reactions. The reaction rate was observed to increase continuously in the course of the ligation process, yet the acceleration of the reaction after the binding of two ligand molecules, observed previously in 100 mM KCl, pH 7, was not observed at other pH values. At pH 6.3, such an acceleration occurred after the binding of three ligands, and at pH 8.5, a large acceleration was observed after the binding of the first ligand molecule. Greater CO binding to the beta chains was observed under all conditions, as in the previous study. The functional heterogeneity of the chains in the first ligation step increased with pH. The chloride concentration did not influence the distribution of the ligand between the alpha and beta chains at pH 6.3 and 8.5. At pH 7, less binding to the alpha chains was observed at 7 mM chloride with respect to 100 mM. The nature of the biliganded component isolated at pH 7 in 100 mM KCl and unresolved by the cryogenic technique was studied using a combination of cryogenic and noncryogenic isoelectric focusing. This component was a mixture of intermediates (alpha beta) (alpha CO beta CO), about 65%, and (alpha beta CO) (alpha CO beta), about 35%. The experimental data were compared with the distributions of intermediates calculated according to the Monod kinetic model assuming rapid and concerted transitions between two quaternary structures at each ligation step. The model provided a qualitative fit of the observed distributions of intermediates at acidic and neutral pH. A large discrepancy between the experimental observations and the predictions of the model was found at alkaline pH. The mechanism of the association reaction is discussed in the light of the available information on the tertiary/quaternary structures of the intermediates, as obtained from the studies of the deoxy/cyanomet model of ligation.

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“…However, it can be presumed that HbS-Providence SCD (if seen in the future) would be generally mild to moderate in severity because HbS-Providence has functional impairment of 2,3-DPG binding with resultant high oxygen affinity. 55 Similar to other high-affinity non-S sickling Hb variants, such as HbS-Travis, HbS-Providence would be expected to ‘auto-protect’ itself from excessive desaturation, polymerization and sickling if inherited as homozygous or double heterozygous SCD in the future.…”

Section: Introductionmentioning

confidence: 99%

Non-S Sickling Hemoglobin Variants: Historical, Genetic, Diagnostic, and Clinical Perspectives

Ahmed¹,

Ibrahim²

2021

Oman Med J

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Apart from hemoglobin-S (HbS), there are other Hb variants (non-S sickling Hb variants) that cause sickle cell disease. However, the profiles of these non-S sickling Hb variants have neither been collated nor harmonized. A literature search revealed 14 non-S sickling Hb variants (HbC-Harlem, HbC-Ziguinchor, HbS-Travis, HbS-Antilles, HbS-Providence, HbS-Oman, HbS-Cameroon, HbS-South End, Hb Jamaica Plain, HbC-Ndjamena, HbS-Clichy, HbS-San Martin, HbS-Wake, and HbS-São Paulo). Generally, the non-S sickling Hb variants are double mutants with the HbS mutation (GAG>GTG: βGlu6Val) and additional β-chain mutations. Consequently, non-S sickling Hb variants give positive solubility and sickling tests, but they differ from HbS with respect to stability, oxygen affinity, and electro-chromatographic characteristics. Similarities and discrepancies between HbS and non-S sickling Hb variants create diagnostic pitfalls that can only be resolved by elaborate electro-chromatographic and/or genetic tests. It is therefore imperative that tropical hematologists should have a thorough understanding of these atypical sickling Hb variants. Collated and harmonized appraisal of the non-S sickling Hb variants have not been previously undertaken. Hence, this paper aims to provide a comprehensive but concise historical, genetic, comparative, diagnostic, and clinical overview of non-S sickling Hb variants. The elaborate techniques often required for precise diagnosis of non-S sickling Hb variants are regrettably not readily available in low resource tropical countries, which paradoxically carry the heaviest burden of sickling disorders. We strongly recommend that tropical countries should upgrade their diagnostic laboratory facilities to avoid misdiagnosis of these atypical Hb mutants.

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Hemoglobin providence. Functional consequences of two alterations of the 2,3-diphosphoglycerate binding site at position beta 82.

Cited by 115 publications

References 32 publications

Hemoglobin Raleigh (β1 valine →acetylalanine). Structural and functional characterization

Hemoglobin Raleigh (β1 valine →acetylalanine). Structural and functional characterization

Modulation of the Association Reaction between Hemoglobin and Carbon Monoxide by Proton and Chloride

Non-S Sickling Hemoglobin Variants: Historical, Genetic, Diagnostic, and Clinical Perspectives

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