| 2,3-Bisphosphoglyceric acid | |
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2,3-Bisphosphoglycerate |
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Other names
2,3-Diphosphoglyceric acid; 2,3-Diphosphoglycerate; 2,3-Bisphosphoglycerate |
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| Identifiers | |
| Abbreviations | 2,3-BPG; 2,3-DPG; 23BPG |
| CAS number | 138-81-8 |
| PubChem | 61 |
| ChemSpider | 161681 , 60 (Racemic) |
| ChEBI | CHEBI:17720 |
| Jmol-3D images | Image 1 |
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| Properties | |
| Molecular formula | C3H8O10P2 |
| Molar mass | 266.04 g mol−1 |
| (verify) (what is: /?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) |
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| Infobox references | |
2,3-Bisphosphoglyceric acid (2,3-Bisphosphoglycerate or 2,3-BPG, also known as 2,3-diphosphoglycerate or 2,3-DPG) is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid (1,3-BPG). 2,3-BPG is present in human red blood cells (RBC; erythrocyte) at approximately 5 mmol/L. It binds with greater affinity to deoxygenated hemoglobin (e.g. when the red cell is near respiring tissue) than it does to oxygenated hemoglobin (e.g., in the lungs) due to spatial changes: 2,3-BPG (whose size is estimated at about 9 angstroms) fits in the deoxygenated hemoglobin configuration (11 angstroms), but not as well in the oxygenated (5 angstroms). It interacts with deoxygenated hemoglobin beta subunits by decreasing their affinity for oxygen, so it allosterically promotes the release of the remaining oxygen molecules bound to the hemoglobin, thus enhancing the ability of RBCs to release oxygen near tissues that need it most. 2,3-BPG is thus an allosteric effector.
Its function was discovered in 1967 by Reinhold Benesch and Ruth Benesch.[1]
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2,3-BPG is formed from 1,3-BPG by the enzyme 2,3-BPG mutase. It can then be broken down by 2,3-BPG phosphatase to form 3-phosphoglycerate. Its synthesis and breakdown are, therefore, a way around a step of glycolysis.
Erythrocytes synthesize and degrade the 2.3-BPG by a diversion of the glycolytic pathway.
The first phase of glucose catabolism includes glucose phosphorylation, isomerization and another phosphorylation to bear fructose-1,6-bisphosphate (F-1,6-BP). Cleavage of fructose 1, 6-bisphosphate yields two molecules: glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP). These two molecules are isomers and are readily converted into one another by triose-phosphate isomerase. The equilibrium of this conversion lies heavily on the side of DHAP for two reasons. Firstly so the glycolytic pathway does not get oversaturated and secondly so that the biochemistry of glycerol can be tied into glycolysis. DHAP can be converted into glycerol when the supply of DHAP is plentiful and glycerol can then be used as a substrate for phase 2 glycolysis when glycolytic intermediates are scarce. The second phase of glucose catabolism converts G3P to 3-phosphoglycerate (3-PG). During the first reaction step, G3P is phosphorylated with a high-energy phosphate and oxidized to 1,3-bisphosphoglycerate (1,3-BPG), through the action of glyceraldehyde 3-phosphate dehydrogenase (G3PD). 1,3-BPG may be dephosphorylated by phosphoglycerate kinase (PGK), generating ATP, or it may be shunted into the Luebering-Rapapport pathway, where bisphosphoglycerate mutase catalyzes the transfer of a phosphoryl group from C1 to C2 of 1,3-BPG, giving 2,3-BPG. 2,3-BPG, the most concentrated organophosphate in the erythrocyte, forms 3-PG by the action of bisphosphoglycerate phosphatase. The concentration on 2,3-BPG varies inversely with the pH, which is inhibitory to catalytic action of bisphosphoglyceromutase. The third phase of anaerobic glucose catabolism involves conversion of 3-PG to pyruvate with the generation of ATP. There is a delicate balance between the need to generate ATP to support energy requirements for cell metabolism and the need to maintain appropriate oxygenation/deoxygenation status of hemoglobin. This balance is maintained by dephosphorilation of 1,3-BPG to 2,3-BPG, which enhances the deoxygenation of hemoglobin. Low pH inhibits the activity of biphosphoglyceromutase and activates bisphosphoglyerate phosphatase, which favors generation of ATP.[2]
When 2,3-BPG binds to deoxyhemoglobin, it acts to stabilize the low oxygen affinity state (T state) of the oxygen carrier. It fits neatly into the cavity of the deoxy- conformation, exploiting the molecular symmetry and positive polarity by forming salt bridges with lysine and histidine residues in the four subunits of hemoglobin. The R state, with oxygen bound to a heme group, has a different conformation and does not allow this interaction. By itself, hemoglobin has sigmoid-like kinetics, which makes easier another subunits’ binding (the first molecule of oxygen helps the following to link).
By selectively binding to deoxyhemoglobin, 2,3-BPG stabilizes the T state conformation, making it harder for oxygen to bind hemoglobin and more likely to be released to adjacent tissues. 2,3-BPG is part of a feedback loop that can help prevent tissue hypoxia in conditions where it is most likely to occur. Conditions of low tissue oxygen concentration such as high altitude (2,3-BPG levels are higher in those acclimated to high altitudes), airway obstruction, or congestive heart failure will tend to cause RBCs to generate more 2,3-BPG in their effort to generate energy by allowing more oxygen to be released in tissues deprived of oxygen. Ultimately, this mechanism increases oxygen release from RBCs under circumstances where it is needed most. This release is potentiated by the Bohr effect in tissues with high energetic demands. Bohr effect is another useful way to solve the affinity problem of the hemoglobin, and it’s related to the pH and the CO2. It’s important to highlight that the behaviour of myoglobin doesn’t work in the same way, as 2,3-BPG has no effect on it.
It is interesting to note that fetal hemoglobin (HbF) exhibits a low affinity for 2,3-BPG, resulting in a higher binding affinity for oxygen. This increased oxygen-binding affinity relative to that of adult hemoglobin (HbA) is due to HbF's having two α/γ dimers as opposed to the two α/β dimers of HbA. The positive histidine residues of HbA β-subunits that are essential for forming the 2,3-BPG binding pocket are replaced by serine residues in HbF γ-subunits. Like that, histidine nº143 gets lost, so 2,3-BPG has difficulties in linking to the fetal hemoglobin, and it looks like the pure hemoglobin. That’s the way O2 flows from the mother to the fetus. As we can see in the following image, fetal hemoglobin has more affinity to oxygen than adult hemoglobin. Moreover, myoglobin has the highest affinity to oxygen.
Differences between myoglobin (Mb), fetal hemoglobin (Hb F), adult hemoglobin (Hb A)
A 2004 study checked the effects of thyroid hormone on 2,3-BPG levels. The result was that the hyperthyroidism modulates in vivo 2,3-BPG content in erythrocytes by changes in the expression of phosphoglycerate mutase (PGM) and 2,3-BPG synthase. This result shows that the increase in the 2,3-BPG content of erythrocytes observed in hyperthyroidism doesn’t depend on any variation in the rate of circulating hemoglobin, but seems to be a direct consequence of the stimulating effect of thyroid hormones on erythrocyte glycolytic activity.[3]
This illness is characterized by a lack of iron, and as 2,3-BPG needs this chemical element to be synthesized, BPG concentration decreases and hemoglobin binds tightly to oxygen. As a result, oxygen release to tissue is reduced.
Recently, scientists have found similarities between low amounts of 2,3-BPG with the occurrence of high altitude pulmonary edema at high altitudes.
| n | Hb (g/dl) | 2,3-BPG (mM) | ||
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| 1 | Normality | 120 | 14.2 ± 1.6 | 4.54 ± 0.57 |
| 2 | Hyperthyroidism | 35 | 13.7 ± 1.4 | 5.66 ± 0.69 |
| 3 | Iron deficiency anaemia | 40 | 10.0 ± 1.7 | 5.79 ± 1.02 |
| 4 | Chronic respiratory disease with hypoxia | 47 | 16.4 ± 2.2 | 5.29 ± 1.13 |
In a 1998 study, erythrocyte 2,3-BPG concentration was analysed during the haemodialysis process. The 2,3-BPG concentration was expressed relative to the haemoglobin tetramer (Hb4) concentration as the 2,3-BPG/Hb4 ratio. Physiologically, an increase in 2.3-BPG levels would be expected to counteract the hypoxia that is frequently observed in this process. Nevertheless, the results show a 2,3-BPG/Hb4 ratio decreased. This is due to the procedure itself: mechanical stress on the erythrocytes is believed to cause the 2,3-BPG escape, which is then removed by haemodialysis. The concentrations of calcium, phosphate, creatinine, urea and albumin didn’t correlate significantly with the total change in 2,3-BPG/Hb4 ratio. However, the ratio sampled just before dialysis correlated significantly and positively with the total weekly dosage of erythropoietin (main hormone in the erythrocytes formation) given to the patients.[4]
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