Hemoglobins primary function is to bind
oxygen that diffuses into the bloodstream from the lungs and then transport it to outlying
tissues where it is released primarily for aerobic respiration. Hemoglobin (Hb)
has to the capacity to bind between 1 and 4 O2
molecules, ranging from fully "desaturated" Hb (deoxyHb) to
fully "saturated" Hb (oxyHb). Oxygen transport is a highly
dynamic process with oxygen continuously being exchanged between the lungs and the
capillaries. As part of this process, Hb also serves to replenish the "oxygen
stores" maintained by myoglobin (Mb), the O2-binding
protein in muscle which releases its oxygen in response to high levels of muscle
activity. Hemoglobin also serves as the conduit for O2 delivery to the fetus
which carries a different form of hemoglobin in it circulation, HbF, or
fetal hemoglobin, as distinguished from HbA, or adult hemoglobin.
The dynamics of oxygen exchange is highly
regulated by several metabolically-derived factors that collectively define the
"oxygen demand" of an individuals tissues. Among the key metabolic factors
regulating the dynamics of hemoglobins oxygen exchange reactions is oxygen itself.
When oxygen levels are high, the capacity of a partially saturated hemoglobin molecule to
bind oxygen disproportionately increases with the number of oxygen molecules it has
already bound. In other words, when environmental oxygen levels are high, partially
saturated hemoglobin molecules exhibit enhanced affinity for binding additional oxygen
molecules, a specialized behavior referred to as cooperativity. Equally
important, hemoglobin also manifests cooperativity in the reverse direction: When
environmental oxygen levels are low, hemoglobins affinity for oxygen drops
disproportionately as fewer and fewer oxygen molecules remain to bind to hemoglobin. Thus,
the cooperative loading or unloading of oxygen from hemoglobin, depending on the
environmental concentration of oxygen,. effectively enhances the oxygen uptake and
delivery capacity of hemoglobin. In this regard, hemoglobin is "supersensitive"
to concentration of it ligand, O2,
Cooperative ligand binding is no accident.
Rather, it is the remarkable product of the evolutionary molding of hemoglobins
structure such that it can adopt more than one functional shape or conformation. In this
regard, hemoglobin is an allosteric protein with an ability to change shapes, or undego
allosteric conformational changes. This property allows hemoglobin to be more responsive
to changes in the environmental oxygen levels. As discussed in detail later on,
hemoglobins cooperative ligand binding behavior can be mathematically approximated
by the following Hill equation, named after its discoverer:
Ya = pO23/(pO23
+ P503) |
Eq. (1) |
Ya, the "saturation fraction" of
hemoglobin which is a quantitative measure of hemoglobins capacity to bind oxygen.
Simply stated, Ya is the average fraction of all available oxygen binding sites in
hemoglobin with oxygen actually bound at equilibrium at a specific partial pressure of
oxygen, pO2. For example, when the saturation fraction equals one, each
hemoglobin molecule is fully saturated with oxygen molecules bound to all four of the
available sites in each molecule. The P50 term in the denominator of this
equation is effectively an equilibrium constant unique to hemoglobin. Empirically, P50
equals the equilibrium pO2 level where hemoglobin molecules are half-saturated,
on the average, or 50% saturated with oxygen (Ya = 0.5).
Without the evolutionarily-molded structure of
hemoglobin that allows for cooperative oxygen binding, it can easily be shown that
hemoglobins saturation fraction for oxygen binding would quantitatively obey a
different equation, one describing noncooperative ligand binding. Namely,
Ya = pO2/(pO2 + P50)
|
Eq. (2) |
Although Eqs. (1) and (2) may not appear to be
that different, the difference has enormous physiological implications for the individual.
As shown later, when the saturation behavior of hemoglobin (i.e., its oxygen binding
capacity) is regulated according to the first equation above, each hemoglobin molecule is
capable of transporting about twice as many oxygen molecules under normal physiological
conditions than would be possible if the saturation behavior obeyed the second equation.
Assuming an individual has 5 liters blood volume with about 5 billion red blood cells per
milliliter, each containing about 280 million hemoglobin molecules, an individuals
blood is estimated to contain about eight-tens of a kilogram of hemoglobin capable of
transporting up to 5 hundredths of a mole of oxygen with each cycle through the lungs.
Without hemoglobins specialized cooperative ligand binding behavior, nearly twice as
much hemoglobin would be needed to transport the same amount of oxygen and this
requirement would presumably require twice the blood volume to accommodate a doubling of
the number of red blood cells for housing the additional hemoglobin. A doubling of the
blood volume and hemoglobin mass would add nearly 12 pounds to an individuals
weight! Clearly, the evolution of hemoglobins cooperative oxygen binding behavior
serves to economize an individuals weight and this presumably improves the
survivability of the species (as well as the self-esteem of its weight-conscious
members!).