This journal paper (The Equilibrium Between Oxygen and Carbonic Acid in Blood by Lawrence J. Henderson) seeks to explain the interaction between oxygen and carbonic acid in the blood by means of the acid-base equilibrium theory. It is hypothesised that oxygen absorption by blood depends upon a chemical combination between oxygen and haemoglobin.
Data from relevant investigations of pioneer researchers - Barcroft, Bohr, Christiansen, Douglas, Haldane and Hasselbach - were visited. The mass law equation was used in calculating values. These values gave an estimate of the probable effect that carbonic acid exerts upon the affinity of haemoglobin for oxygen. It became evident that haemoglobin and carbonic acid are not the only substances involved in the equilibrium reaction. The fluctuation in the calculated values was far from sufficient to account for the variation of bicarbonate with the varying hydrogen ion. It is assumed that there might be acid or base radicals present in the protein portion of the haemoglobin molecule that could be involved in this equilibrium reaction.
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It is inferred that the influence of carbonic acid on the equilibrium between oxygen and haemoglobin may depend upon a chemical reaction involving the protein portion of the haemoglobin molecule that combines with carbonic acid. The union of carbonic acid with haemoglobin is uninfluenced by the presence of oxygen. Further investigation into this process is warranted.
Explanation of Chemistry
Blood is a liquid transport system where important substances that are vital in sustaining life are carried around inside the human body. Of the many substances, this section will focus on the substances involved in the equilibrium between oxygen and carbonic acid in the blood. These substances are as follows:
The discussion that follows would also demonstrate the role of an acid-base reaction (a chemical reaction that occurs between an acid and a base), that is involved in this equilibrium.
Red blood cells collect oxygen in the lungs and distribute it through arteries into the tissues.
Oxygen (O2)is transported in the blood in two ways (Donahoe):
in physical solution in the plasma as dissolved oxygen
in chemical combination with haemoglobin (HbO2) which is the major form of oxygen transport in the blood
The lower carbon dioxide (CO2) concentration and hence higher pH at the lungs promotes the binding of oxygen to haemoglobin and hence the uptake of oxygen. Only a portion of the oxygen carried by the red blood cells is normally unloaded in the tissues. However, vigorous activity can lower the oxygen pressure in the skeletal muscles which causes a large increase in the amount of oxygen released by the red blood cell. This effect is enhanced by the high concentration of carbon dioxide in the muscles and the resulting lower pH (7.2) (Kimball).
At high oxygen concentrations oxyhaemoglobin forms. At low oxygen concentrations oxyhaemoglobin dissociates to haemoglobin and oxygen (Kimball). The oxygen partial pressure acts as the driving force to the chemical combination of haemoglobin and oxygen. Haemoglobin has iron ion attached to its protein so as to produce an oxygen-binding site (Matthews et al).
(Image courtesy of Kimball)
The Haldane effect describes the effect of oxygen on the affinity of haemoglobin for carbon dioxide. That is, deoxygenated haemoglobin has a greater affinity for carbon dioxide than does oxyhaemoglobin. This enhances the ability to load carbon dioxide from the tissues and to be released in the lungs (Donahoe).
Carbon dioxide is a waste product of respiration and its concentration is high in the respiring cell and so it is here that haemoglobin releases oxygen. Like oxygen, the amount of carbon dioxide dissolved in plasma is relatively small (Rhoades & Pflanzer).
The level of carbon dioxide found in the blood is directly related to the metabolic rate of the body. There are many ways of carrying carbon dioxide in our blood: dissolved, combined with water to form carbonic acid as bicarbonate, and in the form of carbamino compounds (carbon dioxide and protein). The carbon dioxide transport system is therefore not limited by the amount of haemoglobin present as in the oxygen transport system (Matthews et al).
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Carbon dioxide combines with water forming carbonic acid which dissociates into a hydrogen ions and bicarbonate ion (Kimball). This reaction in plasma is relatively slow because the enzyme carbonic anhydrase is not present. The majority of the carbon dioxide is transported inside the red blood cell. Since red blood cell contain the enzyme carbonic anhydrase, carbon dioxide is readily hydrated to form H+ + HCO3- the main mechanism for carbon dioxide transport in the blood. Haemoglobin combines with or buffers the free H+ generated (Donahoe).
H2O + CO2 ïƒŸïƒ H2CO3 ïƒŸïƒ H+ + HCO3-
(Image courtesy of Transport of Oxygen in the Blood)
Carbonic acid (H2CO3) is an intermediate step in the transport of carbon dioxide out of the body via respiratory gas exchange. The hydration reaction of carbon dioxide is generally very slow in the absence of a catalyst but red blood cells contain carbonic anhydrase which both increases the reaction rate and dissociates a hydrogen ion (H+) from the resulting carbonic acid leaving bicarbonate (HCO3-) dissolved in the blood plasma. This catalysed reaction is reversed in the lungs where it converts the bicarbonate back into carbon dioxide and allows it to be expelled (Rhoades & Pflanzer).
H2O + CO2 ïƒŸïƒ H2CO3 ïƒŸïƒ H+ + HCO3-
Acidity is directly related to the hydrogen ion concentration (H+). The greater the hydrogen ion concentration, the more acidic the substance. In the body, the accumulation of carbon dioxide leads to an accumulation of hydrogen ions and an increased acidity, as follows (Rhoades & Pflanzer):
H2O + CO2 ïƒŸïƒ H2CO3 ïƒŸïƒ H+ + HCO3-
In the body, acids and bases are kept in a delicate balance by a series of buffers. A buffer is a solution of a weak acid and its salt that prevents marked changes in hydrogen ion concentration. The equilibrium between carbon dioxide and carbonic acid is very important for controlling the acidity of body fluids and the carbonic anhydrase increases the reaction rate by a factor of nearly a billion to keep the fluids at a stable pH (Rhoades & Pflanzer).
The red blood cells contain a pigment called haemoglobin (Hb). Haemoglobin functions efficiently to meet the demands of maintaining equilibrium between oxygen and carbonic acid in the blood (Matthews et al). It consists of 4 polypeptide chains: 2 alpha chains of 141 amino acids and 2 beta chains of 146 amino acids (Kimball). Each polypeptide chain contains 1 heme molecule. Each heme molecule contains a ferrous ion that interacts with oxygen. Therefore, 1 molecule of haemoglobin binds four oxygen molecules forming oxyhaemoglobin. One red blood cell contains 280 million molecules of haemoglobin. The oxygen molecules are carried to individual cells in the body tissue where they are released. The binding of oxygen is a reversible reaction (King).
Hb + 4O2 ïƒŸïƒ Hb.4O2
(Image courtesy of King)
The four disks in the diagram of haemoglobin are the parts of the molecule where the oxygen molecules bind while the four folded sausage shapes represent polypeptide chains (Transport of Oxygen in the Blood).
Haemoglobin can also bind carbon dioxide but to a lesser extent forming carbaminohaemoglobin (Transport of Oxygen in the Blood).
An acidic environment facilitates oxygen release (Matthews et al) thus the presence of carbon dioxide helps the release of oxygen from haemoglobin, this is known as the Bohr effect (Transport of Oxygen in the Blood). Bohr effect - increase in carbon dioxide in blood will cause oxygen to be displaced from the haemoglobin thereby promoting oxygen release in tissues (Kimball).
When carbon dioxide diffuses into the blood plasma and then into the red blood cells in the presence of the catalyst enzyme carbonic anhydrase most carbon dioxide reacts with water in the red blood cells and the following dynamic equilibrium is established (Transport of Oxygen in the Blood)
H2O + CO2 ïƒŸïƒ H2CO3
Carbonic acid dissociates to form hydrogen ions and bicarbonate. This is also a reversible reaction and undissociated carbonic acid, hydrogen ions and bicarbonate exist in dynamic equilibrium with one another (Transport of Oxygen in the Blood)
H2CO3 ïƒŸïƒ H+ + HCO3-
(Image courtesy of Transport of Oxygen in the Blood)
The dissociation of carbonic acid increases the acidity of the blood (low pH). Hydrogen ions then react with oxyhaemoglobin to release bound oxygen and reduce the acidity of the blood. This buffering action allows large quantities of carbonic acid to be carried in the blood without major changes in blood pH (Transport of Oxygen in the Blood)
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Hb.4O2 + H+ ïƒŸïƒ HHb+ + 4O2
(Image courtesy of Kimball)
It is this reversible reaction that accounts for the Bohr effect.
Now the haemoglobin is strongly attracted to carbon dioxide molecules. Carbon dioxide is removed to reduce its concentration in the cell and is transported to the lungs were its concentration is lower. This process is continuous since the oxygen concentration is always higher than the carbon dioxide concentrations in the lungs. The opposite is true in respiring cells (Transport of Oxygen in the Blood).
The journal article is dated, i.e. published in 1920 (90 yrs ago), but is there any significant variation between this article's findings and the current biochemical facts involving the equilibrium between O2and CO2?
This question is justified because it shows the relationship of the dated journal article to current facts.
The journal article inferred that the influence of carbonic acid on the equilibrium between oxygen and haemoglobin may depend upon a chemical reaction involving the protein portion of the haemoglobin molecule that combines with carbonic acid. In addition, the journal article also concluded that the union of carbonic acid with haemoglobin is uninfluenced by the presence of oxygen.
These two results of the journal article still hold true. As discussed under the section 'Explanation of the chemistry', the protein portion of the haemoglobin has a role to play in this equilibrium.
The heme part of haemoglobin has a N-terminal amino group (see structural chemistry below- Kimball). Some of the carbon dioxide becomes bicarbonate and is carried dissolved in the blood plasma. A portion of these bicarbonate reacts directly with haemoglobin, binding to the N-terminal amino groups of the heme to form carbamates
This carbamation reaction allows haemoglobin to aid in the transport of carbon dioxide from the tissues to the lungs. The hydrogen ion released on binding of bicarbonate lowers the pH which then promote the release of oxygen when carbon dioxide is abundant (Matthews et al).
In saying this, the 1920 journal article's inferences have now been proven by biochemistry studies of the late 20th century. Current fact confirms the influence of carbonic acid on the equilibrium between oxygen and haemoglobin through the production of bicarbonate that binds with the N-terminal amino groups of the heme portion of the haemoglobin molecule. In addition, it is also proven that oxygen alone has no sole influence in this equilibrium process (Matthews et al).
How does the biochemical internal environment of the red blood cell achieve equilibrium when the negative charged bicarbonate ion diffuses out of it?
This question is justified because it entails additional equilibrium reaction within the internal environment of the red blood cell.
As mentioned under the section "Explanation of Chemistry", the Bohr effect states that increase in carbon dioxide in the blood will cause oxygen to be displaced from the haemoglobin thereby promoting oxygen release in tissues. Carbon dioxide enters the blood and reduces the blood pH causing oxygen to dissociate from Hb (Bohr effect). This then allows more carbon dioxide to bind to Hb. Hb + CO2 forms carbaminohaemoglobin
CO2 + HbNH2 ïƒŸïƒ HbNH2COOH
In addition to this minor CO2 transport mechanism, CO2 is also able to diffuse from the tissues to the red blood cells where it combines with H2O forming H2CO3 which then immediately dissociates to H+ + HCO3- (major CO2 transport mechanism). Hb immediately binds to H+ before it can leave the red blood cell and lower pH (Hb acts a buffer). HCO3- diffuses into the red blood cell from plasma and the intracellular Chloride (Cl-) diffuses out of the red blood cell into plasma. Vice-versa, the Cl- in the plasma diffuses into the red blood cell once HCO3- is released. There is trading of one anion for another to balance the charge. This anion trading maintains the biochemical equilibrium within the red blood cell (King).
This Cl- -HCO3- exchange (called Chloride shift) again demonstrates the delicate equilibrium that occurs inside the human body. So next time you take your simple next breath, have in mind these complex equilibrium processes that occur inside you in order for you to live.
This reminds me of Genesis 2:7b where it says "and God breathed into man's nostrils the breath of life; and man became a living soul".
Shouldn't the ferrous ion in the heme be oxidising once it combines with O2?
This question is justified because it makes one thinks that the ferrous ion should oxidise once oxygen binds to it; however, the outcome of this ferrous-oxygen binding is that the oxygen is not released readily.
Normally, an oxygen molecule in such close contact with a ferrous (FeII) ion would oxidise the latter to the ferric (FeIII) state. The heme alone does not protect the iron, for heme dissolved free in solution is readily oxidised by oxygen. But in the hydrophobic, protected internal environment provided by the interior of the haemoglobin molecule, the iron does not easily become oxidised. The oxygen is bound, and a temporary electron rearrangement occurs. When the oxygen is released, the iron remains in the ferrous state, able to bind another oxygen (Dickerson & Geis). When the haemoglobin molecule is stored in air, outside the internal cellular environment, the iron does slowly become oxidised. When this oxidation occurs, the binding site is inactivated. Oxygen will not bind and a water molecule occupies the oxygen binding site instead. The protection of an oxygen-binding metal from irreversible oxidation is the functional reason for the existence of haemoglobin. Haemoglobin provides an internal environment in which the first step of an oxidation reaction (the binding of oxygen) is permitted but the final step (oxidation) is blocked (Matthews et al).
Would a defective haemoglobin affect the equilibrium between O2 and CO2?
This question is justified because there are evidence that show abnormal haemoglobin exists in humans that are deleterious to life.
Several hundred recognised abnormal haemoglobins exist within the human population. Some of these abnormal haemoglobins are deleterious and give rise to recognised pathologies. The known deleterious abnormalities are mostly clustered about the heme part and in the vicinity of the alpha and beta chains of polypeptides. Some of these abnormalities would allow for the oxidation process to continue in the haemoglobin molecule leading to unsuccessful binding of oxygen. Individuals carrying such abnormalities would have difficulty in transporting enough oxygen to the tissues (Honig & Adams).