Hb Helsinki: a Variant with a High Oxygen Affinity and a Substitution at a 2,3-DPG Binding Site (&lt;i&gt;β&lt;/i&gt;82 [EF6] Lys→Met)

Ikkala, Esko; Koskela, Juha; Pikkarainen, P; Rahiala, Eeva-Liisa; El‐Hazmi, Mohsen A. F.; Nagai, Kiyoshi; Lang, Anja; Lehmann, H.

doi:10.1159/000207947

Cited by 46 publications

(8 citation statements)

References 27 publications

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“…Since the discovery of the role of 2,3-diphosphoglycerate (DPG)' in regulating oxygen transport (1,2) led to the identification of the binding sites ofanionic cofactors in the hemoglobin molecule (3,4), an understanding of linkage between oxygen binding and cofactor binding has been sought through studies on hemoglobin variants with alterations at the 2,3-DPG binding site (5)(6)(7)(8)(9). Recently Perutz and Poyart (10) reported that low molecular weight compounds, such as 2-(4-chlorophenoxy)-2-methylpropionic acid (clofibric acid) and 2-[4-(2-p-chlorobenzamidethyl)-phenoxy]-2-methylpropionic acid (bezafibrate), have the remarkable ability to modify hemoglobin function in erythrocytes, a finding that opened the way to studies ofthe molecular control of hemoglobin function and its clinical application.…”

Section: Introductionmentioning

confidence: 99%

Hemoglobin Rahere, a human hemoglobin variant with amino acid substitution at the 2,3-diphosphoglycerate binding site. Functional consequences of the alteration and effects of bezafibrate on the oxygen bindings.

Sugihara¹,

Imamura²,

Nagafuchi³

et al. 1985

J. Clin. Invest.

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We encountered an abnormal hemoglobin (Rahere), with a threonine residue replacing the ,682 (EF6) lysine residue at the binding site of 2,3-diphosphoglycerate, which was responsible for overt erythrocytosis in two individuals of a Japanese family. Hemoglobin Rahere shows a lower oxygen affinity on the binding of 2,3-diphosphoglycerate or chloride ions than hemoglobin A. Although a decrease in the positive charge density at the binding sites of 2,3-diphosphoglycerate in hemoglobin Rahere apparently shifts the allosteric equilibrium toward the low affinity state, it greatly diminishes the cofactor effects by anions. The oxygen affinity of the patient's erythrocytes is substantially lowered by the presence of bezafibrate, which combines with sites different from those of 2,3-diphosphoglycerate in either hemoglobin Rahere or hemoglobin A.

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Section: Introductionmentioning

confidence: 99%

Hemoglobin Rahere, a human hemoglobin variant with amino acid substitution at the 2,3-diphosphoglycerate binding site. Functional consequences of the alteration and effects of bezafibrate on the oxygen bindings.

Sugihara¹,

Imamura²,

Nagafuchi³

et al. 1985

J. Clin. Invest.

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“…Presumably arising from this indispensable role in DPG binding, this residue is uniformly conserved in mammalian Hbs (Fig. 3A), with the exception of several heterozygous adult human HbA carriers with substitutions at this position (18,19,31).…”

Section: Resultsmentioning

confidence: 99%

“…1B). This replacement is intriguing not only because β82Lys is invariant among known mammalian Hbs, but because human variants with substitutions at this position display profound alterations in both structural and functional properties [16][17][18][19] . The human Hb Providence (β82Lys→Asn) variant in particular has been well characterized as asparagine at this position progressively undergoes posttranslational deamidation to form aspartic acid (Asp), which over the life-time of the erythrocyte, constitutes ca.…”

Section: Introductionmentioning

confidence: 99%

“…1B), though the specific functional effect(s) of this substitution have not been characterized. This replacement is intriguing not only because β82Lys is invariant among characterized mammalian Hbs, but because human variants with substitutions at this position display profound alterations in both structural and functional properties (16)(17)(18)(19). For example, the human Hb Providence (β82Lys→Asn) variant exhibits a decreased inherent Hb-O2 affinity and markedly reduced sensitivity to the allosteric effectors 2,3-diphosphoglycerate (DPG), Cl -, and H + (16,17,(20)(21)(22)(23), which preferentially bind and stabilize the (low O2 affinity) deoxy-state conformation of the protein.…”

Section: Introductionmentioning

confidence: 99%

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Evolution of an extreme hemoglobin phenotype contributed to the sub-Arctic specialization of extinct Steller’s sea cows

Signore

Fago

Weber

et al. 2022

Preprint

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The extinct Steller’s sea cow (Hydrodamalis gigas; †1768) was a whale-sized marine mammal that manifested profound morphological adjustments to exploit the harsh coastal climate of the North Pacific. Yet despite first-hand accounts of their biology, little is known regarding underlying physiological specializations to this extreme environment. Here, the adult-expressed hemoglobin (Hb) of this species is shown to harbor a fixed amino acid replacement at an otherwise invariant position (β/δ82Lys→Asn) that is predicted to profoundly alter multiple aspects of Hb function. To unravel the functional and evolutionary consequences of this substitution, we recombinantly synthesized Hb proteins of Steller’s sea cow, a H. gigas β/δ82Asn→Lys Hb mutant, the dugong (Dugong dugon), the last common dugongid ancestor, and the Florida manatee (Trichechus manatus). Our detailed functional analyses demonstrate that the Hb–O2 affinity of Steller’s sea cow evolved to become less affected by temperature compared to other sea cows. This phenotype presumably safeguarded O2 delivery to cool peripheral tissues and largely arises from a reduced intrinsic temperature sensitivity of the H. gigas protein owing to the β/δ82Lys→Asn substitution. We further confirm that this same exchange also underlies the secondary evolution of a reduced blood–O2 affinity phenotype that is moreover unresponsive to the intraerythrocytic allosteric effector 2,3-diphosphoglycerate. This radical modification, which augments O2 offloading by the protein, and presumably impacted maternal/fetal O2 exchange, is the first documented example of this phenotype among mammals. Notably, this replacement also increases protein solubility and is consistent with increased Hb concentrations within both the adult and pre-natal circulations that may have contributed to the elevated metabolic (thermoregulatory) requirements and fetal growth rates associated with their cold adaptation.

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“…Among these patients, some carry Hb Helsinki [1] whose structure-function rela tionship has been fully elucidated, whereas others carry hemoglobins whose structures are still un known.…”

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confidence: 99%

Structure and Function of a New Hemoglobin Variant, Hb Meilahti (α<sub>2</sub>β<sub>2</sub> 36(C2)Pro→Thr), Characterized by Mass Spectrometry

Wada

Ikkala²,

Imai³

et al. 1987

Acta Haematol

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An abnormal hemoglobin was found by isoelectric focusing in the blood of a Finnish woman with erythrocytosis. Oxygen equilibrium curves of the patient’s hemolysate indicated the presence of a variant with a very high oxygen affinity. Structural analysis was carried out by mass spectrometry. In the spectrum of the tryptic digest, an abnormal peptide was found at m/zl278 which corresponded to the mass number of the pro-tonated molecular ion of βT4 with 36Pro→Thr substitution. The structure was confirmed by the mass spectrum of the chymotryptic digest

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Hb Helsinki: a Variant with a High Oxygen Affinity and a Substitution at a 2,3-DPG Binding Site (<i>β</i>82 [EF6] Lys→Met)

Cited by 46 publications

References 27 publications

Hemoglobin Rahere, a human hemoglobin variant with amino acid substitution at the 2,3-diphosphoglycerate binding site. Functional consequences of the alteration and effects of bezafibrate on the oxygen bindings.

Hemoglobin Rahere, a human hemoglobin variant with amino acid substitution at the 2,3-diphosphoglycerate binding site. Functional consequences of the alteration and effects of bezafibrate on the oxygen bindings.

Evolution of an extreme hemoglobin phenotype contributed to the sub-Arctic specialization of extinct Steller’s sea cows

Structure and Function of a New Hemoglobin Variant, Hb Meilahti (α<sub>2</sub>β<sub>2</sub> 36(C2)Pro→Thr), Characterized by Mass Spectrometry

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