The affinity of hemoglobin for oxygen is regulated by varying concentration of BPG (2,3-bisphosphoglycerate), which binds to and stabilizes the deoxy form. BPG is a side product of glycoloysis. The question is, whether BPG that regulates hemoglobin affinity is produced in the red cells, or in the tissues that are using the oxygen? If in the red cell, then how is the need for greater unloading of O2 sensed inside the red cell? If in the tissue, how is BPG released from those cells and taken up by the red cell where the hemoglobin is?
2,3-DPG is produced by the red cells, they have all enzymes for glycolysis to make ATP and 2,3-DPG. Oxygen dissociation is regulated through 2,3-DPG, but slightly differently: if oxygen is low in the tissues (lower than in the red cells), depending on the 2,3-DPG concentration, oxygen will go to the tissues. 2,3-DPG does not 'micro-manage' oxygen dissociation in the tissues, rather, it manages that oxygen remains available for all tissues.
That makes sense, that the BPG regulates overall supply to the body, not specific tissues, since on a timescale of hours each cell will be visiting many different tissues. But the question remains, what triggers changes in BPG levels? How does the red cell know that the oxygen level in tissues is too low? Does it sense lower-than-usual O2 levels as it passes through the O2-starved tissues? Or is there a messenger from the tissue, such as NO perhaps, that indicates the tissue needs more oxygen?
If it is sensing O2 levels, it could not be through Hb saturation, because responding to decreased saturation by increasing BPG to deliver more oxygen would create a disastrous positive feedback loop - if BPG is too low and O2 is not dissociating, it would indicate there is plenty of O2 and BPG would be further decreased. There could be another O2 sensor. Or something that detects BPG-free deoxyHb, perhaps by binding at the same site.
O2 levels could drop substantially at high altitude or if circulation is cut off (foot "gone to sleep"). But I think O2 levels in the capillaries are not likely to drop much below 20 torr in response to increased O2 consumption. This is because in normal muscle tissue, the O2 pressure around the mitochondria in the myocytes is around 2 torr. This means a gradient of ~20 tor (OK 18 tor), from red cell to mitochondrion, is required to drive the normal flux. Now if the mitos suddenly start using more O2, so that the concentration in the cell drops to near zero, it would still require 18 torr to deliver the normal flux, and actually increased O2 would be needed in the capillaries to supply the increased demand. Thus sensing a drop in O2 level in the red cell might not be a good way to adjust for increased demand in the tissues.
I read somewhere that hypoxic muscle cells give off more NO, partly because one sink for NO is destruction by oxyMb, and when Mb is deoxygenated this sink is gone so less NO is destroyed. The NO serves to vasodilate the capillaries, resulting in more blood flow. Could it also affect the enzymes involved in BPG production/conversion to increase 2,3-BPG levels in the red cells?
The key to 2,3-DPG function is its differential affinity for oxygenated Hb (low affinity) compared to deoxyHb (higher affinity). In low O2 situations, oxygenated Hb is readily off-loaded from 2,3-DPG and replaced by deoxyHb to be cycled back to the lungs by the red cells.
I had a similar question however I think I may have figured it out based on the answers. Some one please correct me if I am wrong. For cellular metabolism, RBC do not have mitochondria so they rely on glycolysis. Because of this 2,3 - DPG is constantly being produced and in areas of low PO2 it helps keep O2 from binding back to Hb once released... or maybe not. If this is correct then 2,3 - DPG is not really regulated but is always around functions depending on the environment (High PO2 - tissue vs Low PO2 - lungs).
I agree that BPG is not regulated on the time scale of circulation between lungs and tissue, where things like pO2, CO2 and pH drive binding and release. But on a longer time scale, the textbooks say it does respond, for example to decreased O2 pressure at altitudes.
Even cells that have mitochondria still have glycolysis to provide the substrate for ox phos (pyruvate). Maybe if respiration in the tissues begins to slow down for lack of oxygen, the rate limiting step becomes cytochrome oxidase, and intermediates like BPG increase. Then if the BPG could diffuse out of the muscle cells and into the blood cells (That is a big if), it would reduce the affinity resulting in more complete unloading of O2 from Hb and supplying more O2 to the muscle cells.
A recent article describes how the regulation could work based on in-vitro studies as well as describing a physiological study which seems consistent with that mechanism.
http://pubs.acs.org/doi/abs/10.1021/acs.jproteome.6b00733
In fact it depends only on O2 levels in the red cells, no (other) signal from the tissues.
However the explanation in that article does seem (if I understand it correctly) to involve the dissociation state of Hb as the O2 sensor- deoxyHb binds to band 3 displacing glycolytic enzymes, stimulating glycolysis, producing more BPG and stabilizing deoxyHb. And so it would seem suffer from the positive feedback loop mentioned in an earlier answer. Act more like a flip-flop than a linear regulator.
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