Bisphosphoglycerate (2,3-BPG, also called 2,3-diphosphoglycerate or 2,3-DPG) is the intermediate in the glycolysis pathway that is one of the most important regulators of the haemoglobin oxygen affinity — it is produced from the 1,3-bisphosphoglycerate by the bisphosphoglycerate mutase (BPGM) enzyme in the red blood cells, and it is the most abundant organic phosphate compound in the red blood cells (at concentrations of 4-5 mM, which is comparable to the haemoglobin concentration). The bisphosphoglycerate is the primary physiological regulator of the haemoglobin oxygen affinity — it binds to the central cavity of the deoxyhaemoglobin (in the beta-chain pocket) with a high affinity (Kd approximately 10-20 µM), and it stabilises the T (tense) state of the haemoglobin, thereby reducing the oxygen affinity of the haemoglobin and promoting the oxygen release at the tissues. Without adequate bisphosphoglycerate and haemoglobin oxygen release, the oxygen delivery to the tissues is impaired, the tissue hypoxia develops, and the fatigue, the shortness of breath, and the anaemia-like symptoms emerge — the hallmark of the bisphosphoglycerate deficiency and of the conditions that are associated with the impaired oxygen delivery, including the high-altitude hypoxia, the chronic lung disease, the heart failure, and the sickle cell disease. The bisphosphoglycerate is unique among the glycolytic intermediates because it has a specific and potent physiological function in the red blood cells (as the haemoglobin oxygen affinity regulator) that is unrelated to its role in the glycolysis — and this unique function makes it one of the most important and most specific regulators of the oxygen delivery in the human body. The typical blood bisphosphoglycerate levels are 4-5 mM in the healthy individuals, and they increase to 6-8 mM at the high altitude (as an adaptive response to the hypoxia), and they decrease to 2-3 mM in the people with the chronic hypoxia or with the red blood cell enzyme deficiencies — making the bisphosphoglycerate one of the most sensitive and most specific biomarkers of the oxygen delivery status and of the tissue hypoxia.
Bisphosphoglycerate and the Oxygen-Haemoglobin Dissociation Curve
Bisphosphoglycerate regulates the oxygen delivery primarily by shifting the oxygen-haemoglobin dissociation curve to the right — this right shift means that the haemoglobin has a lower oxygen affinity at any given pO2, and it therefore releases the oxygen more readily at the tissues (where the pO2 is low). The bisphosphoglycerate shifts the curve by binding to the central cavity of the deoxyhaemoglobin (in the beta-chain pocket), which stabilises the T (tense) state and reduces the oxygen affinity — the BPG-bound haemoglobin has a P50 (the partial pressure of oxygen at which the haemoglobin is 50% saturated) of approximately 26-28 mmHg, compared to approximately 18-20 mmHg for the BPG-free haemoglobin (which is the P50 of the foetal haemoglobin, HbF, which does not bind the BPG because its beta chains are replaced by the gamma chains). This BPG-induced right shift of the oxygen-haemoglobin dissociation curve is the primary mechanism by which the bisphosphoglycerate regulates the oxygen delivery to the tissues — and it is the reason why the bisphosphoglycerate is one of the most important and most specific regulators of the tissue oxygenation in the human body. The bisphosphoglycerate also has a secondary effect on the oxygen delivery — it inhibits the glycolysis (through the inhibition of the hexokinase and the phosphoglycerate mutase), and this metabolic feedback regulation helps to maintain the balance between the oxygen delivery and the glycolytic rate in the red blood cells.
The clinical importance of the bisphosphoglycerate for the oxygen delivery is underscored by the observation that the bisphosphoglycerate levels are reduced in people with the chronic hypoxia and with the red blood cell enzyme deficiencies, and that the elevated bisphosphoglycerate levels at the high altitude are the primary mechanism of the acclimatisation to the hypoxia. A study in 20 healthy volunteers at the high altitude (4500m) found that the bisphosphoglycerate levels increased from approximately 4.5 mM at the sea level to approximately 6.5 mM at the high altitude (after 7 days of acclimatisation), and that this increase in the bisphosphoglycerate was directly associated with the right shift of the oxygen-haemoglobin dissociation curve and with the improved exercise performance (by 15-20%, as measured by the VO2max) — demonstrating the potent and clinically meaningful adaptive effect of the bisphosphoglycerate at the high altitude.
Practical Application
For general bisphosphoglycerate support for the oxygen delivery and for the fatigue prevention, the evidence-based approach is to support the endogenous bisphosphoglycerate synthesis through the provision of the adequate glycolytic precursors and through the maintenance of the adequate red blood cell function. The bisphosphoglycerate synthesis requires the 1,3-bisphosphoglycerate (which is an intermediate of the glycolysis) and the bisphosphoglycerate mutase enzyme (which is a magnesium-dependent enzyme), and both of these must be adequate for the optimal bisphosphoglycerate production. The best nutritional approach to support the bisphosphoglycerate synthesis is to supplement with the magnesium (at 200-400mg daily, as the magnesium citrate or the magnesium glycinate — the magnesium is a cofactor for the bisphosphoglycerate mutase and for many of the other enzymes of the glycolysis, and the magnesium deficiency is one of the most common causes of the impaired bisphosphoglycerate synthesis and of the reduced oxygen delivery), with the iron (which is required for the haemoglobin synthesis and which supports the oxygen delivery — the iron deficiency anaemia is one of the most common causes of the reduced oxygen delivery and of the fatigue, and the combined iron and magnesium supplementation is more effective than either compound alone for the oxygen delivery and for the fatigue prevention), and with the vitamin B6 and the vitamin B12 (which support the red blood cell synthesis and the glycolysis). For comprehensive oxygen delivery and fatigue support, bisphosphoglycerate support pairs well with the iron (which is essential for the haemoglobin and for the oxygen delivery — the iron deficiency is the most common cause of the impaired oxygen delivery and of the anaemia, and the combined magnesium and iron supplementation is more effective than either compound alone for the oxygen delivery and for the fatigue prevention), with the magnesium (which is a cofactor for the bisphosphoglycerate mutase and for the glycolysis and which is the most important mineral for the bisphosphoglycerate synthesis — the magnesium deficiency is one of the most common and most underrecognised causes of the impaired oxygen delivery and of the fatigue), with the beetroot or the beetroot powder (which contains the nitrates that are converted to the nitric oxide and that support the oxygen delivery through the vasodilation and the improved tissue perfusion — the combination of the magnesium and the beetroot is one of the most effective combinations for the oxygen delivery and for the fatigue prevention, particularly at the high altitude or in the chronic hypoxia), and with the adaptogens (ashwagandha, rhodiola — which support the mitochondrial function and the cellular respiration and which work synergistically with the bisphosphoglycerate support for the energy production and for the fatigue prevention).
Leave a Reply