Bohr Effect Modulation

Background

The Bohr effect facilitates the release of oxygen in the tissues, particularly in tissues with the highest metabolic demand. When a tissue's metabolic rate increases, so does its CO2 production. When released into the bloodstream, CO2 forms bicarbonate and protons—facilitated by carbonic anhydrase present in RBCs—causing the pH to decrease and promoting release of O2 from Hgb. Under anaerobic conditions, muscles generate lactic acid so quickly that pH of the blood passing through the muscles will drop to around 7.2, which causes Hgb to begin releasing roughly 10% more oxygen. The effect size is denoted as Δlog(P₅₀) / ΔpH.

The Bohr effect hinges around allosteric interactions between the hemes of the haemoglobin tetramer. Haemoglobin exists in two conformations: a high-affinity R state and a low-affinity T state. When O2 concentration levels are high, as in the lungs, the R state is favored, enabling the maximum amount of oxygen to be bound to the hemes. In the capillaries, where O2 concentration levels are lower, the T state is favored, in order to facilitate the delivery of oxygen to the tissues. The Bohr effect is dependent on this allostery, as increases in CO2 and H+ help stabilize the T state and ensure greater oxygen delivery to muscles during periods of elevated cellular respiration. When Hgb is in its T state, the N-terminal amino groups of the α-subunits and the C-terminal histidine of the β-subunits are protonated, giving them a positive charge and allowing these residues to participate in ionic interactions with carboxyl groups on nearby residues. These interactions help hold the Hgb in the T state. Decreases in pH (increases in acidity) stabilize this state even more, since a decrease in pH makes these residues even more likely to be protonated, strengthening the ionic interactions.

There is a well described correlation between organism size and the strength of the Bohr effect, with smaller animals exhibiting a much stronger effect. In the 1960s a notable exception was found. Based on their size and weight, many marine mammals were hypothesized to have a very low, almost negligible Bohr effect. However, when their blood was examined, this was not the case. Humpback whales weighing 41,000 kg had an observed Δlog(P₅₀) / ΔpH value of 0.82, which is roughly equivalent to the Bohr effect magnitude in a 0.57 kg guinea pig. This extremely strong Bohr effect is hypothesized to be one of marine mammals' many adaptations for deep, long dives, as it allows for virtually all of the bound oxygen on Hgb to dissociate and supply the whale's body while it is underwater.

Research Idea

Are there human Hgb variants that have a stronger Bohr effect? Could you create such variants? Could you package whale or mouse Hgb in human RBC shells (would xenografted Hgb be immunogenic?) for transfusion in cases where increasing O2 delivery while minimizing volume is paramount? Are there existing drugs that modulate the strength of the Bohr effect in normal human Hgb?