In active muscle, the hemoglobin-oxygen dissociation curve is shifted to the right which enhances the unloading of oxygen. This rightward shift occurs due to the presence of a number of metabolic byproducts that can affect the affinity of hemoglobin for oxygen. This includes an increase in temperature, decrease in pH, increase in PCO2, and an increase in
2,3-bisphosphoglycerate (2,3-BPG). As metabolic activity increases, temperature increases, which alters the structure of hemoglobin in a way that decreases its affinity for oxygen. This decreased affinity allows the hemoglobin to unload more oxygen at the same partial pressure (this is reflected in the rightward shift of the hemoglobin-oxygen dissociation curve). At the same time, increased metabolic activity enhances the production of hydrogen ions (decreasing pH). Hydrogen ions bind to hemoglobin, which release oxygen from the hemoglobin molecule. Thus, as hydrogen ion concentration increases, oxygen is driven off the hemoglobin molecule. This pH-induced alteration in oxygen binding has been termed the Bohr effect. At the same time, oxygen's binding to hemoglobin decreases in the presence of carbon dioxide. Carbon dioxide binds to hemoglobin, forming carbaminohemoglobin, which decreases the affinity of the hemoglobin for oxygen. Since metabolically active tissue produces more carbon dioxide (increasing PCO2), this would tend to increase the unloading of oxygen in active tissue. 2,3-BPG is a metabolic intermediate of glycolysis that is released from erythrocytes (erythrocytes have no aerobic metabolism and therefore rely on anaerobic
glycolysis for energy). The presence of oxyhemoglobin inhibits the activity of the enzymes that produce 2,3-BPG. When oxyhemoglobin levels are reduced, as occurs in active tissue, 2,3-BPG is synthesized. The binding of 2,3-BPG to hemoglobin reduces hemoglobin's affinity for oxygen. Both
anemia and high altitude enhance the production of 2,3-BPG.
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