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.

Sugihara, Jun; Imamura, Takashi; Nagafuchi, Seiho; Bonaventura, Joseph; Bonaventura, Celia; Cashon, Robert E.

doi:10.1172/jci112072

Cited by 13 publications

(11 citation statements)

References 23 publications

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“…This suggests that heterotropic ligands and oxygen binding sites are linked to one another, to a significant extent, within each subunit. Table 2 also supports the previous observation on normal human hemoglobin [8] and abnormal hemoglobin Rahere [16], that CFA and glycerate-2,3-P2 enhance each other's influence on the oxygen binding curve. In order to explore further the structural aspects of this synergistic effect, dichroic spectra and functional properties of dromedary hemoglobin were measured in solutions constituted by different concentrations of CFA and glycerate-2,3-P2 in the presence of 0.1 M chloride.…”

Section: Resultssupporting

confidence: 87%

Multiplicity of interactions between dromedary hemoglobin and solvent components

Bertollini¹,

Santucci²,

Amiconi³

et al. 1988

European Journal of Biochemistry

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The interaction of dromedary hemoglobin with various solvent components [2-(p-chlorophenoxy)-2-1. CFA greatly lowers the oxygen affinity of dromedary hemoglobin. 2. The oxygen-linked CFA binding sites are probably located in the deoxy derivative at the CI cleft, while in the oxy form and in the presence of two other effectors (glycerate-2,3-P2 and chloride) additional, structurally and possibly functionally relevant binding site(s) should be considered. methylpropionic acid (CFA), 2,3-bisphospho-~-glycerate (glycerate-2,3-P2) and chloride] has been studied.3. Both CFA and glycerate-2,3-P2 stabilize the deoxy-like tertiary structure in the oxy derivative. 4. Chloride appears to be fundamental to obtain quaternary structural changes. 5. Interaction energy, retained in the protein when the three ligands (CFA, glycerate-2,3-P2 and chloride) are bound to the oxy form, favours intermediates not stable if only one or two allosteric effector(s) is (are) present on the protein.6. The oxygen affinity appears to be related to both tertiary and quaternary structural changes, while cooperativity is largely invariant with solvent conditions.In conclusion, the functional properties of dromedary hemoglobin do not depend in any simple way on the variety of stabilized conformations.The structure of a hemoglobin molecule is determined in part by its solution environment. Thus, the addition of a non-heme ligand to the system is expected to produce some alterations in the energetic balance of its immediate surroundings (tertiary conformational changes); in its turn such modification can propagate (depending on the ligand and experimental conditions) to the inter-subunit contacts with consequent movement of chains relative to one another (quaternary conformational changes). The relationships between local, direct effects of non-heme ligand binding and gross, indirect structural changes in regions of the protein remote from the site of non-heme ligand association were recently investigated in hemoglobin from Cumelus dromedurius [l -31. This protein is an a2P2 tetramer characterized by: (a) an amino acidic sequence with all residues considered relevant for the functional properties of human hemoglobin [4], and (b) two distinct binding sites for polyanions, which modulate as a function of their concentration the structural and functional properties of the protein [l -3, 5, 61.In particular, previous results on dromedary hemoglobin indicate that: (a) the effect of polyanions on the conformation appears to be essentially local; and (b) the presence of chloride ions is necessary in order to induce quaternary changes in the Correspondence to G. Amiconi, Dipartimento Di Scienze Biochimiche, Universita Degli Studi di Roma 'La Sapienza', Piazzale Aldo Moro, 5, 1-00185 Roma, ItalyAbbreviations. CFA, chlofibric acid = 2-@-chlorophenoxy)-2-methylpropionic acid; giycerate-2,3-Pz or Grip2, 2,3-bIsphospho-~-glycerate.polyanion -protein system (at least in the ferric derivative at acid pH). Apart from the physiological relevance of these effects, su...

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Section: Resultssupporting

confidence: 87%

Multiplicity of interactions between dromedary hemoglobin and solvent components

Bertollini¹,

Santucci²,

Amiconi³

et al. 1988

European Journal of Biochemistry

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“…Consistent with this expectation, the intrinsic O 2 affinity of eastern mole Hb is ~2.8-fold lower than that of coast mole Hb in the physiological pH range (Figure 2 ). Finally, the strongly suppressed DPG sensitivities of human Hbs with residue replacements at β82 (e.g., Hb Rahere β82Lys→Thr and Hb Providence β82Lys→Asn/Asp; [ 32 , 33 ]) are qualitatively similar in magnitude to that of eastern mole Hb (Figure 2 , Table 1 ). In this regard, it is notable that eastern moles also possess an unusual δ3Leu→Met substitution in the N-terminal region of the δ-chains (Figure 4 ).…”

Section: Discussionmentioning

confidence: 81%

Molecular basis of a novel adaptation to hypoxic-hypercapnia in a strictly fossorial mole

et al. 2010

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BackgroundElevated blood O2 affinity enhances survival at low O2 pressures, and is perhaps the best known and most broadly accepted evolutionary adjustment of terrestrial vertebrates to environmental hypoxia. This phenotype arises by increasing the intrinsic O2 affinity of the hemoglobin (Hb) molecule, by decreasing the intracellular concentration of allosteric effectors (e.g., 2,3-diphosphoglycerate; DPG), or by suppressing the sensitivity of Hb to these physiological cofactors.ResultsHere we report that strictly fossorial eastern moles (Scalopus aquaticus) have evolved a low O2 affinity, DPG-insensitive Hb - contrary to expectations for a mammalian species that is adapted to the chronic hypoxia and hypercapnia of subterranean burrow systems. Molecular modelling indicates that this functional shift is principally attributable to a single charge altering amino acid substitution in the β-type δ-globin chain (δ136Gly→Glu) of this species that perturbs electrostatic interactions between the dimer subunits via formation of an intra-chain salt-bridge with δ82Lys. However, this replacement also abolishes key binding sites for the red blood cell effectors Cl-, lactate and DPG (the latter of which is virtually absent from the red cells of this species) at δ82Lys, thereby markedly reducing competition for carbamate formation (CO2 binding) at the δ-chain N-termini.ConclusionsWe propose this Hb phenotype illustrates a novel mechanism for adaptively elevating the CO2 carrying capacity of eastern mole blood during burst tunnelling activities associated with subterranean habitation.

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“…The DPG anion binds to a specific lysine residue on hemoglobin, and this shifts the hemoglobin-binding site between high-and lowaffinity states (245). Similarly, oxygen-induced binding of hemoglobin to band 3 of erythrocytes results in an increase in anion exchange at the microcirculation (226).…”

Section: 5)mentioning

confidence: 99%

Targeted Delivery of Hormones to Tissues by Plasma Proteins

Pardridge

1998

Comprehensive Physiology

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The sections in this article are: Organ Physiology of Solute Exchange Through Capillary Walls Quantitation of Capillary Solute Transport: Kety‐Renkin‐Crone Equation Capillary Geometry, Organ Blood Flow, and Capillary Transit Times Capillary Membrane Permeability Capillary Physiology of Steroid and Thyroid Hormone Transport Plasma Protein–Binding Kinetics Dissociation‐Limited Transport Enhanced Dissociation Mechanism of Plasma Protein–Mediated Transport Transcapillary Transport of Protein–Hormone Complex Physiology‐Based Model of Cellular Bioavailable Hormone Experimental Attempts to Measure Free Cellular Hormone Molecular Physiology of Hormone‐Binding Plasma Proteins Albumin Prealbumin (Transthyretin) Thyroid Hormone–Binding Globulin Corticosteroid‐Binding Globulin Sex Hormone–Binding Globulin α 1 ‐Acid Glycoprotein (Orosomucoid) Summary

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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.

Cited by 13 publications

References 23 publications

Multiplicity of interactions between dromedary hemoglobin and solvent components

Multiplicity of interactions between dromedary hemoglobin and solvent components

Molecular basis of a novel adaptation to hypoxic-hypercapnia in a strictly fossorial mole

Targeted Delivery of Hormones to Tissues by Plasma Proteins

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