Human Physiology, 14th edition (2016)

Negative

feedback

2.

Less O 2

delivery to

the tissues

Increased O 2

unloading to

the tissues

Red Blood Cells

Lower affinity of

hemoglobin for

oxygen

Less oxyhemoglobin

Less inhibition of

2,3-DPG production

Increased 2,3-DPG

1. Low PO 2 at high altitude

Respiratory Physiology 563

previously described, whereas fetal hemoglobin has two gamma

chains in place of the beta chains (gamma chains differ from beta

chains in 37 of their amino acids). Normal adult hemoglobin in

the mother (hemoglobin A) is able to bind to 2,3-DPG. Fetal

hemoglobin, or hemoglobin F, by contrast, cannot bind to

2,3-DPG and thus has a higher affinity for oxygen than does

hemoglobin A. Because hemoglobin F can have a higher per-

cent oxyhemoglobin than hemoglobin A at a given P^ O 2 , oxy-

gen is transferred from the maternal to the fetal blood as these

two come into close proximity in the placenta (chapter 20; see

fig. 20.46).

Effect of 2,3-DPG on Oxygen

Transport

Mature red blood cells lack both nuclei and mitochondria. With-
out mitochondria they cannot respire aerobically; the very cells
that carry oxygen are the only cells in the body that cannot use it!
Red blood cells must thus obtain energy through the anaerobic
metabolism of glucose. At a certain point in the glycolytic path-
way, a “side reaction” occurs in the red blood cells that results
in a unique product— 2,3-diphosphoglyceric acid (2,3-DPG).
The enzyme that produces 2,3-DPG is inhibited by oxy-
hemoglobin. When the oxyhemoglobin concentration is
decreased, therefore, the production of 2,3-DPG is increased.
This increase in 2,3-DPG production can occur when the total
hemoglobin concentration is low (in anemia) or when the P^ O 2
is low (at a high altitude; fig.  16.35 ). The 2,3-DPG binds to
deoxyhemoglobin and makes it more stable, thereby favor-
ing the conversion of oxyhemoglobin to deoxyhemoglobin.
Because of this, a greater proportion of oxyhemoglobin will
unload its oxygen and be converted to deoxyhemoglobin at
each P^ O 2 value. An increased concentration of 2,3-DPG in red
blood cells thus increases oxygen unloading ( table  16.9 ) and
shifts the oxyhemoglobin dissociation curve to the right.

Anemia

When the total blood hemoglobin concentration falls below
normal in anemia, each red blood cell produces increased
amounts of 2,3-DPG. A normal hemoglobin concentration
of 15 g per 100 ml unloads about 4.5 ml O 2 per 100 ml at
rest, as previously described. If the hemoglobin concentration
were reduced by half, you might expect that the tissues would
receive only half the normal amount of oxygen (2.25 ml O 2 per
100 ml). However, an amount as great as 3.3 ml O 2 per 100 ml
is actually unloaded to the tissues under these conditions. This
occurs as a result of a rise in 2,3-DPG production that causes a
decrease in the affinity of hemoglobin for oxygen.

Fetal Hemoglobin

The effects of 2,3-DPG are also important in the transfer of
oxygen from maternal to fetal blood. In an adult, hemoglobin
molecules are composed of two alpha and two beta chains as

Factor Affinity Position of Curve Comments

↓pH Decreased Shift to the right Called the Bohr effect; increases oxygen delivery during hypercapnia

↑Temperature Decreased Shift to the right Increases oxygen unloading during exercise and fever

↑2,3-DPG Decreased Shift to the right Increases oxygen unloading when there is a decrease in total hemoglobin

or total oxygen content; an adaptation to anemia and high-altitude living

Table 16.9 | Factors That Affect the Affinity of Hemoglobin for Oxygen and the Position
of the Oxyhemoglobin Dissociation Curve

Figure 16.35 2,3-DPG promotes the unloading

of oxygen to the tissues. Because production of 2,3-DPG

is inhibited by oxyhemoglobin, a reduction in the red blood

cell content of oxyhemoglobin (as occurs at the low PO 2 of

high altitude) increases 2,3-DPG production. This lowers

the affinity of hemoglobin for oxygen (decreases the bond

strength), so that more oxygen can be unloaded. The dashed

arrow and negative sign indicate the completion of a negative

feedback loop.