Mechanisms of hemoglobin adaptation to high altitude hypoxia

Abstract

Evidence from a number of vertebrate taxa suggests that modifications of hemoglobin (Hb) function may often play a key role in mediating an adaptive response to high altitude hypoxia. The respiratory functions of Hb are a product of the protein's intrinsic O(2)-binding affinity and its interactions with allosteric effectors such as protons, chloride ions, CO(2), and organic phosphates. Here we review several case studies involving high altitude vertebrates where it has been possible to identify specific mechanisms of Hb adaptation to hypoxia. In addition to comparative studies of Hbs from diverse animal species, functional studies of human Hb mutants also suggest that there is ample scope for evolutionary adjustments in Hb-O(2) affinity through alterations of the equilibrium constants of O(2) binding to deoxy- and oxyHb or through changes in the allosteric equilibrium constants for the transition between the deoxy- and oxyHb quaternary structures. It may be the case that certain evolutionary paths are followed more often than others simply because they are subject to less stringent pleiotropic constraints.

FIG. 1.

O₂ equilibrium curves showing the theoretical influence of a change in Hb–O₂ affinity on blood O₂ transport under conditions of moderate hypoxia (open symbols) and severe hypoxia (filled symbols). Each curve is a plot of the O₂ saturation of Hb (vertical axis) versus blood (horizontal axis), with paired values for arterial and venous blood connected by solid lines. For each pair of arterial and venous points, the for venous blood () is marked by a vertical gray line that extends to the horizontal axis. The sigmoid O₂ equilibrium curves are shown for high, intermediate, and low Hb–O₂ affinities; of blood at which the O₂ saturation of Hb is at 50%. Each change in Hb–O₂ affinity produces a shift in , but the of arterial blood () is assumed to remain constant. In this graph, is the difference in O₂ concentration between arterial and mixed venous blood, and is the corresponding arterial–venous difference in . , the blood O₂ capacitance coefficient, is defined as the ratio (= the slope of the line connecting the arterial and venous points on the O₂ equilibrium curve). The interrelationships of these parameters are summarized by the following Fick's equation: , where is the total O₂ consumption and Vb is the total cardiac bloodflow. The product is the circulatory conductance of O₂ in the bloodstream. Note that under conditions of moderate hypoxia the right-shifted curve produces the greatest and results in a less severe drop in , the overall index of tissue oxygenation. By contrast, under severe hypoxia, the left-shifted curve produces the greatest values of and . When the kinetics of O₂ transfer across the alveolar gas–blood barrier become a limiting step (diffusion limitation), a left-shifted O₂ equilibrium curve may also be advantageous under conditions of less severe hypoxia (Bencowitz et al., ; Bouverot, 1985).

FIG. 2.

Three-dimensional structure of the Hb tetramer (left) and a detailed view of the heme–ligand complex (right). The distal histidine (E7) and proximal histidine (F8) residues are shown above and below the heme plane, respectively.

FIG. 3.

The α₂β₂ dimer (one-half of a functional Hb tetramer) shown in a side view. The intradimer α₂β₂ packing contacts are shown in green and the residues participating in interdimer (α₁β₂ and α₂β₂)sliding contacts are shown in purple.

FIG. 4.

Dot representation of van der Waals radii at an intradimer α₁β₁ contact in human Hb (left) and bar-headed goose Hb (right). Note that in the bar-headed goose Hb the replacement of Ala for Pro at the α119(H2) residue position results in a loss of atomic contact between the α₁ and β₁ subunits. The disruption of this interchain van der Waals contact destabilizes the T-state deoxyHb quaternary structure and therefore results in an increased Hb–O₂ affinity, because the allosteric equilibrium is shifted in favor of the R-state oxyHb structure.

FIG. 5.

Binding of 2,3-DPG in the central cavity between the β₁ and β₂ chains of deoxyHb. Also shown (lower-left corner) is an intrachain salt bridge that is formed in deoxyHb between the imidazole ring of the N-terminal β146(HC3)His and the negatively charged β94(FG1)Asp. This bond increases the affinity of FG1 Asp for protons and therefore contributes to the Bohr effect. The protons are released upon transition to R-state oxyHb.

FIG. 6.

Homology-based structural model of deer mouse oxyHb showing the location of five amino acid replacement polymorphisms that span the E-helix domain of the α-chain subunit. Two charge-changing substitutions at α50(CD8) and α64(E13) are highlighted in the inset figure.