Bohr effect

The Bohr effect is a physiological phenomenon first described in 1904 by the Danish physiologist Christian Bohr: hemoglobin's oxygen binding affinity (see oxygen–haemoglobin dissociation curve) is inversely related both to acidity and to the concentration of carbon dioxide. That is, the Bohr effect refers to the shift in the oxygen dissociation curve caused by changes in the concentration of carbon dioxide or the pH of the environment. Since carbon dioxide reacts with water to form carbonic acid, an increase in CO2 results in a decrease in blood pH, resulting in hemoglobin proteins releasing their load of oxygen. Conversely, a decrease in carbon dioxide provokes an increase in pH, which results in hemoglobin picking up more oxygen. The Bohr effect is a physiological phenomenon first described in 1904 by the Danish physiologist Christian Bohr: hemoglobin's oxygen binding affinity (see oxygen–haemoglobin dissociation curve) is inversely related both to acidity and to the concentration of carbon dioxide. That is, the Bohr effect refers to the shift in the oxygen dissociation curve caused by changes in the concentration of carbon dioxide or the pH of the environment. Since carbon dioxide reacts with water to form carbonic acid, an increase in CO2 results in a decrease in blood pH, resulting in hemoglobin proteins releasing their load of oxygen. Conversely, a decrease in carbon dioxide provokes an increase in pH, which results in hemoglobin picking up more oxygen. In the early 1900s, Christian Bohr was a professor at the University of Copenhagen in Denmark, already well known for his work in the field of respiratory physiology. He had spent the last two decades studying the solubility of oxygen, carbon dioxide, and other gases in various liquids, and had conducted extensive research on haemoglobin and its affinity for oxygen. In 1903, he began working closely with Karl Hasselbalch and August Krogh, two of his associates at the university, in an attempt to experimentally replicate the work of Gustav von Hüfner, using whole blood instead of haemoglobin solution. Hüfner had suggested that the oxygen-haemoglobin binding curve was hyperbolic in shape, but after extensive experimentation, the Copenhagen group determined that the curve was in fact sigmoidal. Furthermore, in the process of plotting out numerous dissociation curves, it soon became apparent that high partial pressures of carbon dioxide caused the curves to shift to the right. Further experimentation while varying the CO2 concentration quickly provided conclusive evidence, confirming the existence of what would soon become known as the Bohr effect. There is some more debate over whether Bohr was actually the first to discover the relationship between CO2 and oxygen affinity, or whether the Russian physiologist Bronislav Verigo beat him to it, allegedly discovering the effect in 1898, six years before Bohr. While this has never been proven, Verigo did in fact publish a paper on the haemoglobin-CO2 relationship in 1892. His proposed model was flawed, and Bohr harshly criticized it in his own publications. Another challenge to Bohr's discovery comes from within his lab. Though Bohr was quick to take full credit, his associate Krogh, who invented the apparatus used to measure gas concentrations in the experiments, maintained throughout his life that he himself had actually been the first to demonstrate the effect. Though there is some evidence to support this, retroactively changing the name of a well-known phenomenon would be extremely impractical, so it remains known as the Bohr effect. The Bohr effect increases the efficiency of oxygen transportation through the blood. After hemoglobin binds to oxygen in the lungs due to the high oxygen concentrations, the Bohr effect facilitates its release in the tissues, particularly those tissues in most need of oxygen. When a tissue's metabolic rate increases, so does its carbon dioxide waste production. When released into the bloodstream, carbon dioxide forms bicarbonate and protons through the following reaction: Although this reaction usually proceeds very slowly, the enzyme carbonic anhydrase (which is present in red blood cells) drastically speeds up the conversion to bicarbonate and protons. This causes the pH of the blood to decrease, which promotes the dissociation of oxygen from haemoglobin, and allows the surrounding tissues to obtain enough oxygen to meet their demands. In areas where oxygen concentration is high, such as the lungs, binding of oxygen causes haemoglobin to release protons, which recombine with bicarbonate to eliminate carbon dioxide during exhalation. These opposing protonation and deprotonation reactions occur at an equal rate, resulting in little overall change in blood pH. The Bohr effect enables the body to adapt to changing conditions and makes it possible to supply extra oxygen to tissues that need it the most. For example, when muscles are undergoing strenuous activity, they require large amounts of oxygen to conduct cellular respiration, which generates CO2 (and therefore HCO3− and H+) as byproducts. These waste products lower the pH of the blood, which increases oxygen delivery to the active muscles. Carbon dioxide is not the only molecule that can trigger the Bohr effect. If muscle cells aren't receiving enough oxygen for cellular respiration, they resort to lactic acid fermentation, which releases lactic acid as a byproduct. This increases the acidity of the blood far more than CO2 alone, which reflects the cells' even greater need for oxygen. In fact, 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 haemoglobin to begin releasing roughly 10% more oxygen. The magnitude of the Bohr effect is usually given by the formula Δ log ⁡ ( P 50 ) Δ pH { extstyle {scriptstyle Delta log(P_{50}) over Delta { ext{pH}}}} . Here, P50 refers to the partial pressure of oxygen when 50% of haemoglobin's binding sites are occupied. The formula is obtained by plotting the logarithm of this measurement on a graph at various pH levels, yielding a line with slope equal to Δ log ⁡ ( P 50 ) Δ pH { extstyle {scriptstyle Delta log(P_{50}) over Delta { ext{pH}}}} . Bohr effect strength exhibits an inverse relationship with the size of an organism: the magnitude increases as size and weight decreases. For example, mice possess a very strong Bohr effect, with a Δ log ⁡ ( P 50 ) Δ pH { extstyle {scriptstyle Delta log(P_{50}) over Delta { ext{pH}}}} value of 0.96, which requires relatively minor changes in H+ or CO2 concentrations, while elephants require much larger changes in concentration to achieve a much weaker effect ( Δ log ⁡ ( P 50 ) Δ pH = 0.38 ) { extstyle left({scriptstyle Delta log(P_{50}) over Delta { ext{pH}}}=0.38 ight)} . The Bohr effect hinges around allosteric interactions between the hemes of the haemoglobin tetramer, a mechanism first proposed by Max Perutz in 1970. Haemoglobin exists in two conformations: a high-affinity R state and a low-affinity T state. When oxygen 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 oxygen 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. This is evidenced by the fact that myoglobin, a monomer with no allostery, does not exhibit the Bohr effect. Haemoglobin mutants with weaker allostery may exhibit a reduced Bohr effect. For example, in Hiroshima variant haemoglobinopathy, allostery in haemoglobin is reduced, and the Bohr effect is diminished. As a result, during periods of exercise, the mutant haemoglobin has a higher affinity for oxygen and tissue may suffer minor oxygen starvation.