Structural Biochemistry/Protein function/Heme group/Hemoglobin/Bohr Effect

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The Bohr effect was first discovered by a physiologist Christian Bohr in 1904. This effect explains how hydrogen ions and carbon dioxide affect the affinity of oxygen in Hemoglobin. If pH was lower than it normally was (normal physiological pH is 7.4), then the hemoglobin does not bind oxygen as well. In other words, the lower the pH, the more Hydrogen ions, the higher the carbon dioxide level and the LESS affinity Hemoglobin has for oxygen. The opposite explains: the higher the pH, the lower the H ion concentration, the lower the carbon dioxide level, and the GREATER affinity hemoglobin has for oxygen. The binding of oxygen to hemoglobin in the lungs is not affected by changing the pH and the oxygen will continue to be loaded normally. This does not prove to be true in tissues however, and a change in the pH results in a lower percent saturation of hemoglobin. More oxygen is delivered to tissues at a lower pH even when the amount of oxygen available remains unchanged.

Levels of Oxygen in a Tissue

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How can it be determined if a tissue is more active and thus requires more oxygen? One way to determine this is by the amount of oxygen present in a tissue. If a tissue is using more oxygen, then one would expect that the amount of oxygen would be lower. When this is the case, more oxygen is delivered to the tissue. Another indicator that a tissue has a high metabolic rate, meaning that there is a need for increased oxygen delivery, is the production of Carbon Dioxide. When a tissue is more active, the amount of carbon dioxide produced will be increased. Carbon dioxide reacts with water as is shown in the following equation:

CO2+ H2O <---------> H+ + HCO-3

This shows that as the amount of carbon dioxide increases, more H+ is formed and the pH will decrease. In other words, the more CO2 present, the more H+ is formed (so the lower the pH; remember pH is inversely related to the H+ concentration by the equation pH = -log[H+])

A lower pH in the blood is suggestive of an increased carbon dioxide concentration which in turn, is suggestive of a more active tissue that requires more oxygen. According to Bohr, the lower pH will cause hemoglobin to deliver more oxygen. If the amount of oxygen and pH should drop together, even more oxygen will be delivered than if only one of the these factors were changed. If the pH of the tissues should rise due to a drop in the carbon dioxide concentration, then less oxygen will be delivered.

The Bohr Effect is dependent upon cooperativity between the hemoglobin tetramer and the Heme group; it is key to note that although myoglobin and hemoglobin are very similar, myoglobin does not exhibit this effect because Myoglobin, a monomer, does not exhibit any cooperative interactions. If the hemoglobin's cooperativity is weak, then the Bohr effect will in turn be low.

This phenomenon explains why Hemoglobin can readily release oxygen in human tissue. The pH of the tissue is much lower than in the human lungs, so the blood will want to release the oxygen creating hemoglobin in its t-state. Once the blood travels back to the lungs, where the pH is higher, the blood will pick up more oxygen for transport. Myoglobin holds onto its oxygen in the tissue because it is not influenced by the Bohr effect. On average, the hemoglobin can release 66% of its oxygen, whereas myoglobin only releases about 7%.

If a person were to increase their physical activity, and take in more oxygen. The transport of oxygen per red blood cell would increase as well because the CO2 levels would rise in the body, leading to a lower pH in the tissues. Another factor that will also affect the binding of oxygen to hemoglobin is temperature, which may be affected due to physical activity among many other factors. A more active tissue will be producing more heat and will be warmer. This increased temperature may lead to changes in hemoglobin's affinity to oxygen in a similar fashion as would be expected from a decrease in pH.

The affinity that hemoglobin has on oxygen is decreased when the pH of the solution is decreased. When the solution is at a lower pH, hemoglobin tends to release more oxygen because it doesn't have as much affinity to keep the oxygen binded to the heme group. The main reason for this is shown by what occurs in deoxyhemoglobin. If the pH is lowered the histidine can be protonated. This triggers salt bridges to form between the now-protonated and positively charged imidazole group on the histidine with the negatively charged carboxylate group on a nearby aspartate. This causes the stabilizing of the deoxyhemoglobin or T state. This causes the T state, which has less affinity for oxygen, to be more prominent which pushes for oxygens to be released from hemoglobin.

Effect of pH on the oxygen affinity of Hemoglobin

Carbon Dioxide

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The presence of Carbon dioxide gives rise to the release of oxygen from hemoglobin. The first way it does this is that at high concentrations the carbon dioxide reduces the pH. This occurs due to the fact that carbon dioxide reacts with water and forms carbonic acid, and carbonic acid dissociate to release proton H and bicarbonate ion, so it will decrease pH. This reaction is sped up very quickly with an enzyme present in red blood cells, Carbonic anhydrase. Carbonic acid is a relatively strong acid, so it tends to dissociate causing an increase in hydrogen ion presence. This results in a decrease in pH. The second way it aids in releasing oxygen from hemoglobin is that there is a direct interaction that carbon dioxide has with the hemoglobin itself. What occurs is that carbon dioxide stabilizes the deoxyhemoglobin form by reacting with the terminal amino groups. It basically forms a carbamate group which is negatively charged. These negatively charged groups participate in salt bridges. Due to this the deoxyhemoglobin or T state is stabilized pushing for oxygen to be released from hemoglobin.

Formation of Carbamate group; Due to this reaction occurring deoxyhemoglobin is stabilized therefore releasing oxygen