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The Bohr effect is a 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.[1] 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,[2] 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.
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Bohr effect : What is Bohr effect and Mechanism of Bohr effect
Transcription
So we've talked a little bit about the lungs and the tissue, and how there's an interesting relationship between the two where they're trying to send little molecules back and forth. The lungs are trying to send, of course, oxygen out to the tissues. And the tissues are trying to figure out a way to efficiently send back carbon dioxide. So these are the core things that are going on between the two. And remember, in terms of getting oxygen across, there are two major ways, we said. The first one, the easy one is just dissolved oxygen, dissolved oxygen in the blood itself. But that's not the major way. The major way is when oxygen actually binds hemoglobin. In fact, we call that HbO2. And the name of that molecule is oxyhemoglobin. So this is how the majority of the oxygen is going to get delivered to the tissues. And on the other side, coming back from the tissue to the lungs, you've got dissolved carbon dioxide. A little bit of carbon dioxide actually, literally comes just right in the plasma. But that's not the majority of how carbon dioxide gets back. The more effective ways of getting carbon dioxide back, remember, we have this protonated hemoglobin. And actually remember, when I say there's a proton on the hemoglobin, there's got to be some bicarb floating around in the plasma. And the reason that works is because when they get back to the lungs, the proton, that bicarb, actually meet up again. And they form CO2 and water. And this happens because there's an enzyme called carbonic anhydrase inside of the red blood cells. So this is where the carbon dioxide actually gets back. And of course, there's a third way. Remember, there's also some hemoglobin that actually binds directly to carbon dioxide. And in the process, it forms a little proton as well. And that proton can go do this business. It can bind to a hemoglobin as well. So there's a little interplay there. But the important ones I want you to really kind of focus in on are the fact that hemoglobin can bind to oxygen. And also on this side, that hemoglobin actually can bind to protons. Now, the fun part about all this is that there's a little competition, a little game going on here. Because you've got, on the one side, you've got hemoglobin binding oxygen. And let me draw it twice. And let's say this top one interacts with a proton. Well, that protons going to want to snatch away the hemoglobin. And so there's a little competition for hemoglobin. And here, the oxygen gets left out in the cold. And the carbon dioxide does the same thing, we said. Now, we have little hemoglobin bound to carbon dioxide. And it makes a proton in the process. But again, it leave oxygen out in the cold. So depending on whether you have a lot of oxygen around, if that's the kind of key thing going on, or whether you have a lot of these kinds of products the proton or the carbon dioxide. Depending on which one you have more of floating around in the tissue in the cell, will determine which way that reaction goes. So keeping this concept in mind, then I could actually step back and say, well, I think that oxygen is affected by carbon dioxide and protons. I could say, well, these two, carbon dioxide and protons, are actually affecting, let's say, are affecting the, let's say, the affinity or the willingness of hemoglobin to bind, of hemoglobin for oxygen. That's one kind of statement you could make by looking at that kind of competition. And another person come along and they say, well, I think oxygen actually is affecting, depending on which one, which perspective you take. You could say, oxygen is affecting maybe the affinity of hemoglobin for the carbon dioxide and proton of hemoglobin for CO2 and protons. So you could say it from either perspective. And what I want to point out is that actually, in a sense, both of these are true. And a lot of times we think, well, maybe it's just saying the same thing twice. But actually, these are two separate effects. And they have two separate names. So the first one, talking about carbon dioxide and protons, their effect is called the Bohr effect. So you might see that word or this description. This is the Bohr effect. And the other one, looking at it from the other prospective, looking at it from oxygen's perspective, this would be the Haldane effect. That's just the name of it, Haldane effect. So what is the Bohr effect and the Haldane effect? Other than simply saying that the things compete for hemoglobin. Well, let me actually bring up a little bit of the canvas. And let's see if I can't diagram this out. Because sometimes I think a little diagram would really go a long way in explaining these things. So let's see if I can do that. Let's use a little graph and see if we can illustrate the Bohr effect on this graph. So this is the partial pressure of oxygen, how much is dissolved in the plasma. And this is oxygen content, which is to say, how much total oxygen is there in the blood. And this, of course, takes into account mostly the amount of oxygen that's bound to hemoglobin. So as I slowly increase the partial pressure of oxygen, see how initially, not too much is going to be binding to the hemoglobin. But eventually as a few of the molecules bind, you get cooperativity. And so then, slowly the slope starts to rise. And it becomes more steep. And this is all because of cooperativity. Oxygen likes to bind where other oxygens have already bound. , And then it's going to level off. And the leveling off is because hemoglobin is starting to get saturated. So there aren't too many extra spots available. So you need lots and lots of oxygen dissolved in the plasma to be able to seek out and find those extra remaining spots on hemoglobin. So let's say we choose two spots. One spot, let's say, is a high amount of oxygen dissolved in the blood. And this, let's say, is a low amount of oxygen dissolved in the blood. I'm just kind of choosing them arbitrarily. And don't worry about the units. And if you were to think of where in the body would be a high location, that could be something like the lungs where you have a lot of oxygen dissolved in blood. And low would be, let's say, the thigh muscle where there's a lot of CO2 but not so much oxygen dissolved in the blood. So this could be two parts of our body. And you can see that. Now, if I want to figure out, looking at this curve how much oxygen is being delivered to the thigh, then that's actually pretty easy. I could just say, well, how much oxygen was there in the lungs, or in the blood vessels that are leaving the lungs. And there's this much oxygen in the blood vessels leaving the lungs. And there's this much oxygen in the blood vessels leaving the thigh. So the difference, whenever oxygen is between these two points, that's the amount of oxygen that got delivered. So if you want to figure out how much oxygen got delivered to any tissue you can simply subtract these two values. So that's the oxygen delivery. But looking at this, you can see an interesting point which is that if you wanted to increase the oxygen delivery. Let's say, you wanted for some reason to increase it, become more efficient, then really, the only way to do that is to have the thigh become more hypoxic. As you move to the left on here, that's really becoming hypoxic, or having less oxygen. So if you become more hypoxic, then, yes, you'll have maybe a lower point here, maybe a point like this. And that would mean a larger oxygen delivery. But that's not ideal. You don't want your thighs to become hypoxic. That could start aching and hurting. So is there another way to have a large oxygen delivery without having any hypoxic tissue, or tissue that has a low amount of oxygen in it. And this is where the Bohr effect comes into play. So remember, the Bohr effect said that, CO2 and protons affect the hemoglobin's affinity for oxygen. So let's think of a situation. I'll do it in green. And in this situation, where you have a lot of carbon dioxide and protons, the Bohr effect tells us that it's going to be harder for oxygen to bind hemoglobin. So if I was to sketch out another curve, initially, it's going to be even less impressive, with less oxygen bound to hemoglobin. And eventually, once the concentration of oxygen rises enough, it will start going up, up, up. And it does bind hemoglobin eventually. So it's not like it'll never bind hemoglobin in the presence of carbon dioxide and protons. But it takes longer. And so the entire curve looks shifted over. These conditions of high CO2 and high protons, that's not really relevant to the lungs. The lungs are thinking, well, for us, who cares. We don't really have these conditions. But for the thigh, it is relevant because the thigh has a lot of CO2. And the thigh has a lot of protons. Again, remember, high protons means low pH. So you can think of it either way. So in the thigh, you're going to get, then, a different point. It's going to be on the green curve not the blue curve. So we can draw it at the same O2 level, actually being down here. So what is the O2 content in the blood that's leaving the thigh? Well, then to do it properly, I would say, well, it would actually be over here. This is the actual amount. And so O2 deliver is actually much more impressive. Look at that. So O2 delivery is increased because of the Bohr effect. And if you want to know exactly how much it's increased, I could even show you. I could say, well, this amount from here down to here. Literally the vertical distance between the green and the blue lines. So this is the extra oxygen delivered because of the Bohr effect. So this is how the Bohr effect is so important at actually helping us deliver oxygen to our tissues. So let's do the same thing, now, but for the Haldane effect. And to do this, we actually have to switch things around. So our units and our axes are going to be different. So we're going to have the amount of carbon dioxide there. And here, we'll do carbon dioxide content in the blood. So let's think through this carefully. Let's first start out with increasing the amount of carbon dioxide slowly but surely. And see how the content goes up. And here, as you increase the amount of carbon dioxide, the content is kind of goes up as a straight line. And the reason it doesn't take that S shape that we had with the oxygen is that there's no cooperativity in binding the hemoglobin. It just goes up straight. So that's easy enough. Now, let's take two points like we did before. Let's take a point, let's say up here. This will be a high amount of CO2 in the blood. And this will be a low amount of CO2 in the blood. So you'd have a low amount, let's say right here, in what part of the tissue? Well, low CO2, that sounds like the lungs because there's not too much CO2 there. But high CO2, it probably is the thighs because the thighs like little CO2 factories. So the thigh has a high amount and the lungs have a low amount. So if I want to look at the amount of CO2 delivered, we'd do it the same way. We say, OK, well, the thighs had a high amount. And this is the amount of CO2 in the blood, remember. And this is the amount of CO2 in the blood when it gets to the lungs. So the amount of CO2 that was delivered from the thigh to the lungs is the difference. And so this is how much CO2 delivery we're actually getting. So just like we had O2 delivery, we have this much CO2 delivery. Now, read over the Haldane effect. And let's see if we can actually sketch out another line. In the presence of high oxygen, what's going to happen? Well, if there's a lot of oxygen around, then it's going to change the affinity of hemoglobin for carbon dioxide and protons. So it's going to allow less binding of protons and carbon dioxide directly to the hemoglobin. And that means that you're going to have less CO2 content for any given amount of dissolved CO2 in the blood. So the line still is a straight line, but it's actually, you notice, it's kind of slope downwards. So where is this relevant? Where do you have a lot of oxygen? Well, it's not really relevant for the thighs because the thighs don't have a lot of oxygen. But it is relevant for the lungs. It is very relevant there. So now you can actually say, well, let's see what happens. Now that you have high O2, how much CO2 delivery are you getting? And you can already see it. It's going to be more because now you've got this much. You've got going all the way over here. So this is the new amount of CO2 delivery. And it's gone up. And in fact, you can even show exactly how much it's gone up by, by simply taking this difference. So this difference right here between the two, this is the Haldane effect. This is the visual way that you can actually see that Haldane effect. So the Bohr effect and the Haldane effect, these are two important strategies our body has for increasing the amount of O2 delivery and CO2 delivery going back and forth between the lungs and the tissues.
Experimental discovery
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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.[3] He had spent the last two decades studying the solubility of oxygen, carbon dioxide, and other gases in various liquids,[4] and had conducted extensive research on haemoglobin and its affinity for oxygen.[3] 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.[1] Hüfner had suggested that the oxygen-haemoglobin binding curve was hyperbolic in shape,[5] 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.[4] Further experimentation while varying the CO2 concentration quickly provided conclusive evidence, confirming the existence of what would soon become known as the Bohr effect.[1]
Controversy
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[6] While this has never been proven, Verigo did in fact publish a paper on the haemoglobin-CO2 relationship in 1892.[7] His proposed model was flawed, and Bohr harshly criticized it in his own publications.[1]
beat him to it, allegedly discovering the effect in 1898, six years before Bohr.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,[8] 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.[4]
Physiological role
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.[2] 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 in equilibrium 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.[2]
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Strength of the effect and body size
The magnitude of the Bohr effect is usually given by the slope of the vs curve where, P50 refers to the partial pressure of oxygen when 50% of haemoglobin's binding sites are occupied. The slope is denoted: where denotes change. That is, denotes the change in and the change in . 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 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 .[9]
Mechanism
Allosteric interactions
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The Bohr effect hinges around allosteric interactions between the hemes of the haemoglobin tetramer, a mechanism first proposed by Max Perutz in 1970.[10] 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.[2] 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.[11]
T-state stabilization
When hemoglobin 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 haemoglobin 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. In the R state, the ionic pairings are absent, meaning that the R state's stability increases when the pH increases, as these residues are less likely to stay protonated in a more basic environment. The Bohr effect works by simultaneously destabilizing the high-affinity R state and stabilizing the low-affinity T state, which leads to an overall decrease in oxygen affinity.[2] This can be visualized on an oxygen-haemoglobin dissociation curve by shifting the whole curve to the right.
Carbon dioxide can also react directly with the N-terminal amino groups to form carbamates, according to the following reaction:
CO2 forms carbamates more frequently with the T state, which helps to stabilize this conformation. The process also creates protons, meaning that the formation of carbamates also contributes to the strengthening of ionic interactions, further stabilizing the T state.[2]
Special cases
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Marine mammals
An exception to the otherwise well-supported link between animal body size and the sensitivity of its haemoglobin to changes in pH was discovered in 1961.[12] Based on their size and weight, many marine mammals were hypothesized to have a very low, almost negligible Bohr effect.[9] However, when their blood was examined, this was not the case. Humpback whales weighing 41,000 kilograms had an observed value of 0.82, which is roughly equivalent to the Bohr effect magnitude in a 0.57 kg guinea pig.[9] 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 haemoglobin to dissociate and supply the whale's body while it is underwater.[12] Examination of other marine mammal species supports this. In pilot whales and porpoises, which are primarily surface feeders and seldom dive for more than a few minutes, the was 0.52, comparable to a cow,[9] which is much closer to the expected Bohr effect magnitude for animals of their size.[12]
Carbon monoxide
Another special case of the Bohr effect occurs when carbon monoxide is present. This molecule serves as a competitive inhibitor for oxygen, and binds to haemoglobin to form carboxyhaemoglobin.[13] Haemoglobin's affinity for CO is about 210 times stronger than its affinity for O2,[14] meaning that it is very unlikely to dissociate, and once bound, it blocks the binding of O2 to that subunit. At the same time, CO is structurally similar enough to O2 to cause carboxyhemoglobin to favor the R state, raising the oxygen affinity of the remaining unoccupied subunits. This combination significantly reduces the delivery of oxygen to the tissues of the body, which is what makes carbon monoxide so toxic. This toxicity is reduced slightly by an increase in the strength of the Bohr effect in the presence of carboxyhemoglobin. This increase is ultimately due to differences in interactions between heme groups in carboxyhemoglobin relative to oxygenated hemoglobin. It is most pronounced when the oxygen concentration is extremely low, as a last-ditch effort when the need for oxygen delivery becomes critical. However, the physiological implications of this phenomenon remain unclear.[13]
See also
References
- ^ a b c d Bohr; Hasselbalch, Krogh. "Concerning a Biologically Important Relationship - The Influence of the Carbon Dioxide Content of Blood on its Oxygen Binding".
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(help) - ^ a b c d e f Voet, Donald; Judith G. Voet; Charlotte W. Pratt (2013). Fundamentals of Biochemistry: Life at the Molecular Level (4th ed.). John Wiley & Sons, Inc. p. 189.
- ^ a b Irzhak, L. I. (2005). "Christian Bohr (On the Occasion of the 150th Anniversary of His Birth)". Human Physiology. 31 (3): 366–368. doi:10.1007/s10747-005-0060-x. ISSN 0362-1197.
- ^ a b c Edsall, J. T. (1972). "Blood and Hemoglobin: The Evolution of Knowledge of Functional Adaptation in a Biochemical System. Part I: The Adaptation of Chemical Structure to Function in Hemoglobin". Journal of the History of Biology. 5 (2): 205–257. doi:10.1007/bf00346659. JSTOR 4330576. PMID 11610121. S2CID 751105.
- ^ G. Hüfner, "Ueber das Gesetz der Dissociation des Oxyharmoglobins und über einige daran sich knupfenden wichtigen Fragen aus der Biologie," [On the Law of the Dissociation of Oxyharmoglobin, and on some important questions arising from biology]. Arch. Anat. Physiol. (in German) (Physiol. Abtheilung) (1890), 1-27.
- ^ "Вериго эффект - это... Что такое Вериго эффект?" [Verigo effect is... What is the Verigo effect?]. Словари и энциклопедии на Академике (in Russian). Retrieved 2016-11-08.
- ^ B. Werigo, "Zur Frage uber die Wirkung des Sauerstoffs auf die Kohlensaureausscheidung in den Lungen," [The question about the effect of oxygen on the secretion of carbonic acid in the lungs]. Pflügers Arch. ges. Physiol. (in German), 51 (1892), 321-361.
- ^ A. Krogh, "Apparat und Methoden zur Bestimmung der Aufnahme von Gasen im Blute bei verschiedenen Spannungen der Gase," [Apparatus and methods for the determination of the absorption of gases in the blood at different tensions of the gases]. Skand. Arch. Physiol. (in German), 16 (1904), 390-401.
- ^ a b c d Riggs, Austen (1960-03-01). "The Nature and Significance of the Bohr Effect in Mammalian Hemoglobins". The Journal of General Physiology. 43 (4): 737–752. doi:10.1085/jgp.43.4.737. ISSN 0022-1295. PMC 2195025. PMID 19873527.
- ^ Perutz, Max (1998-01-15). Science is Not a Quiet Life. World Scientific. ISBN 9789814498517.
- ^ Olson, JS; Gibson QH; Nagel RL; Hamilton HB (December 1972). "The ligand-binding properties of hemoglobin Hiroshima ( 2 2 146asp )". The Journal of Biological Chemistry. 247 (23): 7485–93. doi:10.1016/S0021-9258(19)44551-1. PMID 4636319.
- ^ a b c Riggs, Austen (1961-04-01). "Bohr Effect in the Hæmoglobins of Marine Mammals". Nature. 190 (4770): 94–95. Bibcode:1961Natur.190...94R. doi:10.1038/190094a0. PMID 13741621. S2CID 26899569.
- ^ a b Hlastala, M. P.; McKenna, H. P.; Franada, R. L.; Detter, J. C. (1976-12-01). "Influence of carbon monoxide on hemoglobin-oxygen binding". Journal of Applied Physiology. 41 (6): 893–899. doi:10.1152/jappl.1976.41.6.893. ISSN 0021-8987. PMID 12132.
- ^ Hall, John E. (2010). Guyton and Hall Textbook of Medical Physiology (12th ed.). Philadelphia, Pa: Saunders/Elsevier. p. 502. ISBN 978-1416045748.
External links
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