RBCs contain enormous numbers of hemoglobin molecules. Hemoglobin is a protein consisting of four polypeptide subunits, each of which surrounds a heme group—an iron-containing ring structure that can reversibly bind a molecule of O₂. Thus each hemoglobin molecule can bind and release up to four O₂ molecules, enabling the blood to carry a large amount of O₂ to the body’s tissues.

Hemoglobin’s ability to pick up or release O₂ depends on the P_O2 in its environment. When the P_O2 of the blood plasma is high, as it usually is in the lung capillaries, each hemoglobin molecule can carry its maximum load of four O₂ molecules. As the blood circulates through the rest of the body, it releases some of the O₂ it carries when it encounters lower P_O2 values in tissues.

The relationship between P_O2 and the amount of O₂ bound to hemoglobin is not linear but S-shaped (sigmoidal). The hemoglobin–oxygen binding/dissociation curve reflects interactions between the four subunits of the hemoglobin molecule. At low P_O2 values, only one subunit will bind an O₂ molecule (Figure 48.12A). When it does so, the shape of that subunit changes, altering the quaternary structure of the entire hemoglobin molecule. That structural change makes it easier for the other subunits to bind an O₂ molecule; that is, their O₂ affinity is increased. Therefore a smaller increase in P_O2 is necessary to get the hemoglobin molecule to bind a second O₂ molecule (that is, to become 50% saturated) than was necessary to get it to bind one O₂ molecule (to become 25% saturated). This change in affinity is reflected in the increased steepness of the O₂-binding curve. The influence of O₂ binding/dissociation by one subunit on the O₂ affinity of the other subunits is called positive cooperativity.

Once the third O₂ molecule is bound, the relationship seems to change, as a larger increase in P_O2 is required for the hemoglobin to reach 100 percent saturation. This upper bend of the sigmoid curve is due to a probability phenomenon. The closer we get to having all subunits occupied, the less likely it is that any particular O₂ molecule will find a place to bind. Therefore it takes a relatively greater P_O2 to achieve 100 percent saturation.

The O₂-binding/dissociation properties of hemoglobin help get O₂ to the tissues that need it most (Figure 48.12B). In the lungs, where the P_O2 is about 100 mm Hg, hemoglobin is 100 percent saturated. The P_O2 in blood returning to the heart from the body (at rest) is usually about 40 mm Hg. You can see that at this P_O2 the hemoglobin is still about 75 percent saturated. This means that as the blood circulates around the body, it releases only about one in four of the O₂ molecules it carries. This system seems inefficient, but because the hemoglobin keeps 75 percent of its O₂ in reserve, it can meet the demands of highly active tissues.

When a tissue becomes starved of O₂ and its local P_O2 falls below 40 mm Hg, the hemoglobin flowing through that tissue is on the steep portion of its binding/dissociation curve. That means relatively small decreases in P_O2 below 40 mm Hg will result in the release of lots of O₂ to the tissue. Thus hemoglobin is very effective in making O₂ available to tissues precisely when and where it is needed most.

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The O₂ transport function of hemoglobin can rapidly and tragically be disrupted by a common by-product of incomplete combustion: carbon monoxide (CO). If CO from a faulty heating system, engine exhaust, or burning charcoal accumulates in a closed space, the results can be deadly. Because CO binds to hemoglobin with a 240-fold higher affinity than O₂, it can prevent hemoglobin from transporting O₂. In the United States, up to 500 people die each year from CO poisoning.