HB Kodaira [B146(HC3)HIS→GLN]: A New β Chain Variant with an Amino Acid Substitution at the C-Terminus

Harano, Teruo; Harano, Keiko; Kushida, Y; Imai, Katsunori; Nishinakamura, Ryuichi; Matsunaga, Taizo

doi:10.3109/03630269209005681

Cited by 13 publications

(6 citation statements)

References 15 publications

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“…Enzymatic removal of the ␤ chain COOHterminal residues (145-Tyr and 146-His) from human HbA drastically reduces the Bohr effect and cooperativity but increases O 2 affinity, confirming its role in stabilizing the T state relative to the R state (12,43,49,56). Moreover, abnormal human Hb with ␤146His replaced by a wide range of other residues [viz., by Asp in Hb Hiroshima 2 (38,64), Pro in Hb York (48,55), Tyr in Hb Bologna-St. Orsola (also called Hb Halamshire) (50,52), Gln in Hb Kodaira (33), Leu in Hb Cowtown (76), and Arg in Hb Cochin-Port Royal (87)] show a similar reduction in the Bohr effect, and generally decreased heme-heme cooperativity and increased O 2 affinities.…”

Section: Co 2 Effectsmentioning

confidence: 88%

Lack of conventional oxygen-linked proton and anion binding sites does not impair allosteric regulation of oxygen binding in dwarf caiman hemoglobin

Weber

Fago

Malte

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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In contrast to other vertebrate hemoglobins (Hbs) whose high intrinsic O2 affinities are reduced by red cell allosteric effectors (mainly protons, CO2, organic phosphates, and chloride ions), crocodilian Hbs exhibit low sensitivity to organic phosphates and high sensitivity to bicarbonate (HCO3(-)), which is believed to augment Hb-O2 unloading during diving and postprandial alkaline tides when blood HCO3(-) levels and metabolic rates increase. Examination of α- and β-globin amino acid sequences of dwarf caiman (Paleosuchus palpebrosus) revealed a unique combination of substitutions at key effector binding sites compared with other vertebrate and crocodilian Hbs: β82Lys→Gln, β143His→Val, and β146His→Tyr. These substitutions delete positive charges and, along with other distinctive changes in residue charge and polarity, may be expected to disrupt allosteric regulation of Hb-O2 affinity. Strikingly, however, P. palpebrosus Hb shows a strong Bohr effect, and marked deoxygenation-linked binding of organic phosphates (ATP and DPG) and CO2 as carbamate (contrasting with HCO3(-) binding in other crocodilians). Unlike other Hbs, it polymerizes to large complexes in the oxygenated state. The highly unusual properties of P. palpebrosus Hb align with a high content of His residues (potential sites for oxygenation-linked proton binding) and distinctive surface Cys residues that may form intermolecular disulfide bridges upon polymerization. On the basis of its singular properties, P. palpebrosus Hb provides a unique opportunity for studies on structure-function coupling and the evolution of compensatory mechanisms for maintaining tissue O2 delivery in Hbs that lack conventional effector-binding residues.

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Section: Co 2 Effectsmentioning

confidence: 88%

Lack of conventional oxygen-linked proton and anion binding sites does not impair allosteric regulation of oxygen binding in dwarf caiman hemoglobin

Weber

Fago

Malte

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The C-terminal α141Arg does not directly contribute to the Bohr effect [the pK a (acid dissociation constant) of Arg is 12.0, so it is overwhelmingly protonated at pH7.4], but it contributes indirectly to the Cl --dependent Bohr effect by facilitating the Cl --assisted charge stabilization of the free-NH 2 terminus of α1Val. Accordingly, human HbA mutants that have the same residues as the golden-mantled ground squirrel (Hb Nunobiki, α141Arg→Cys and Hb Kodaira, β146His→Gln) are characterized by a marked reduction in the alkaline Bohr effect (Harano et al, 1992;Kwiatkowski and Noble, 1987;Shimasaki, 1985). In the case of the β-chain carboxy terminus, the positive charge on β146His is stabilized in the T-state by the negative charge of β94Asp and, at least in human HbA, it has been estimated that the oxygenationlinked deprotonation of β146His accounts for most of the Bohr effect (Fang et al, 1999;Lukin and Ho, 2004;Perutz, 1983;Perutz et al, 1985).…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges

Revsbech

Tufts

Projecto-Garcia

et al. 2013

Journal of Experimental Biology

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SUMMARYSemi-fossorial ground squirrels face challenges to respiratory gas transport associated with the chronic hypoxia and hypercapnia of underground burrows, and such challenges are compounded in species that are native to high altitude. During hibernation, such species must also contend with vicissitudes of blood gas concentrations and plasma pH caused by episodic breathing. Here, we report an analysis of hemoglobin (Hb) function in six species of marmotine ground squirrels with different altitudinal distributions. Regardless of their native altitude, all species have high Hb-O 2 affinities, mainly due to suppressed sensitivities to allosteric effectors [2,3-diphosphoglycerate (DPG) and chloride ions]. This suppressed anion sensitivity is surprising given that all canonical anion-binding sites are conserved. Two sciurid species, the golden-mantled and thirteen-lined ground squirrel, have Hb-O 2 affinities that are characterized by high pH sensitivity and low thermal sensitivity relative to the Hbs of humans and other mammals. The pronounced Bohr effect is surprising in light of highly unusual amino acid substitutions at the C-termini that are known to abolish the Bohr effect in human HbA. Taken together, the high O 2 affinity of sciurid Hbs suggests an enhanced capacity for pulmonary O 2 loading under hypoxic and hypercapnic conditions, while the large Bohr effect should help to ensure efficient O 2 unloading in tissue capillaries. In spite of the relatively low thermal sensitivities of the sciurid Hbs, our results indicate that the effect of hypothermia on Hb oxygenation is the main factor contributing to the increased blood-O 2 affinity in hibernating ground squirrels.

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“…Nevertheless, the phenotypic manifestation of the two mutations should be identical since both CAG and CAA code for glutamine. In the original report of Harano et al, [1] the patient was anemic (Hb 7.9 g=L) but he suffered from chronic renal failure which could have masked the phenotype of this variant. On the other hand, our patient was mildly polycythemic, which is characteristic of Hb variants with increased oxygen affinity.…”

Section: Marcel Dekker Inc • 270 Madison Avenue • New York Ny 10016mentioning

confidence: 96%

“…CAA)]. [1] However, the underlying nucleotide change is different. Hb Kodaira results from a point mutation of CAC !…”

Section: Marcel Dekker Inc • 270 Madison Avenue • New York Ny 10016mentioning

confidence: 99%

Hb KODAIRA II: A HIGH OXYGEN AFFINITY VARIANT WITH A NOVEL MUTATION IN THEβ-GLOBIN GENE AND PHENOTYPIC IDENTITY TO Hb KODAIRA

Law

et al. 2002

Hemoglobin

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A 35-year-old lady with a history of good health was diagnosed as having impaired glucose tolerance during pregnancy. A hemoglobin (Hb) variant was incidentally detected when her blood was assayed for Hb A 1c by automatic cation exchange high performance liquid chromatography (HPLC). Peripheral blood examination showed mild polycythemia: Hb 15.5 g=dL (normal 11.7-14.9 g=dL), RBC 5.57610 12 =L (normal 3.9-5.0610 12 =L), PCV 0.46 L=L (normal 0.35-0.45 L=L), MCV 82.7 fL (normal 82-97 fL), MCH 27.7 pg (normal 27-33 pg) and MCHC 33.5 g=dL (normal 32-35 g=dL), with normal red cell morphology. Hb analysis using HPLC showed 45.8% Hb A, 2.7% Hb A 2 (normal 1.5-3.5%) and a slightly increased Hb F value of 1.6% (normal <1%) which was probably related to her pregnant state. The rest (49.9%) was made up of a Hb variant. The variant co-migrated with Hb A in cellulose acetate electrophoresis at pH 8.3, but was separable from the latter at pH 6.0 (Fig. 1). Globin chain electrophoresis at pH 8.8 showed that it was probably a b chain variant (data not shown).The raised Hb level, normal red cell morphology and absence of clinical symptoms of anemia were suggestive of a Hb variant with high oxygen affinity. DNA sequencing of the b-globin gene revealed that the patient was heterozygous * Corresponding

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HB Kodaira [B146(HC3)HIS→GLN]: A New β Chain Variant with an Amino Acid Substitution at the C-Terminus

Cited by 13 publications

References 15 publications

Lack of conventional oxygen-linked proton and anion binding sites does not impair allosteric regulation of oxygen binding in dwarf caiman hemoglobin

Lack of conventional oxygen-linked proton and anion binding sites does not impair allosteric regulation of oxygen binding in dwarf caiman hemoglobin

Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges

Hb KODAIRA II: A HIGH OXYGEN AFFINITY VARIANT WITH A NOVEL MUTATION IN THEβ-GLOBIN GENE AND PHENOTYPIC IDENTITY TO Hb KODAIRA

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