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Cause of higher affinity of fetal haemoglobin for oxygen
A pregnant woman is able to transfer oxygen to her fetus because fetal hemoglobin has a greater affinity for oxygen than does adult hemoglobin. Why is the affinity of fetal hemoglobin for oxygen higher?
A. The tense form of hemoglobin is more prevalent in the circulation of the fetus.
B. There is less 2, 3-BPG in the fetal circulation as compared to maternal circulation.
C. Fetal hemoglobin binds 2, 3-BPG with fewer ionic bonds than the adult form.
D. The Bohr Effect is enhanced in the fetus.
E. The oxygen-binding curve of fetal hemoglobin is shifted to the right.
The right answer is -C.
The enhanced uptake of maternal oxygen by fetal Hb is due to less binding of 2, 3 BPG with fetal Hb.
It is not due to more prevalence of tense form of fetal hemoglobin in the circulation.
It is also not due to less 2, 3 BPG in the fetal circulation, the Bohr Effect is not enhanced in the fetus and the oxygen -binding curve of fetal Hb is also not shifted to the right.
2,3-BPG, is the most concentrated organophosphate in the erythrocytes. It is synthesized from Glucose by Luebering-Rapoport pathway which is a diversion from the main glycolytic pathway.
In erythrocytes, the reaction catalyzed by phosphoglycerate kinase may be bypassed, to some extent by the reaction of bisphosphoglycerate mutase, which catalyzes the conversion of 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate, followed by hydrolysis to 3-phosphoglycerate and Pi, catalyzed by 2,3-bisphosphoglycerate phosphatase (Figure-1). This alternative pathway involves no net yield of ATP from glycolysis. However, it does serve to provide 2,3-bisphosphoglycerate, which binds to hemoglobin, decreasing its affinity for oxygen, and so making oxygen more readily available to tissues .
Figure-1- RL Shunt- Formation and breakdown of 2,3-bisphosphoglycerate.
Significance of 2,3 BPG
In Hb A (adult Hb) when 2, 3-BPG binds to deoxyhemoglobin, it acts to stabilize the low oxygen affinity state (T state) of the oxygen carrier, exploiting the molecular symmetry and positive polarity by forming salt bridges with lysine and histidine residues in the four subunits of hemoglobin (figure-2).
The R state, with oxygen bound to a heme group, has a different conformation and does not allow this interaction. 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.
Figure-2- Oxygen binding and unloading. 2,3 BPG being negatively charged binds to positively charged Histidine and Lysine residues of hemoblobin, stabilizing the tight binding state (T) or low affinity state that promotes oxygen unloading.
2,3-BPG can help to 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, anemia 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.
This release is potentiated by the Bohr effect in tissues with high energetic demands.
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 (figure-3).
Figure-3- Adult Hb and fetal Hb.
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 so 2; 3-BPG has difficulties in linking to the fetal hemoglobin, hence the affinity of fetal hemoglobin for O2 increases. That’s the way O2 flows from the mother to the fetus (figure-4).
Figure-4-Flow of oxygen from maternal Hemoglobin to fetal hemoglobin. Maternal Hb has low affinity for oxygen (due to bound 2,3 BPG) whereas the affinity of fetal Hb for oxygen is more due to unavailable binding sites for 2,3 BPG.
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