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Amir Golnabi
ENGS 166 – Spring 2008
Paper #1 – 04/02/08
The Role of Hemoglobin in Regulation of Oxygen and Carbon Dioxide
Our life depends on a continuous supply of oxygen. We all know that oxygen is
essential in the breathing process. Living cells in our bodies are the site of enormous
biochemical activities, known as metabolism, and appropriate level of oxygen is critical
to support metabolism. Oxygen is used as an electron receptor in mitochondria to
generate energy for the cells. But, why does the oxygen need to be carried into the tissues
continuously? It is very important to keep in mind that the tissues have no storage system
for oxygen. As a result, they rely on a constant supply, and any failure, even for a few
minutes, can cause fatality.
How is the oxygen transported to the tissues in need of oxygen? The answer lies
in Hemoglobin. Hemoglobin is the protein that carries oxygen from the lungs to the
tissues and in return, takes the carbon dioxide that has been produced in the cells, as a
result of cellular respiration, back to the lungs. Hemoglobin is found in the red blood
cells. Each red blood cell (RBC) contains about 280 million hemoglobin molecules. But,
why does the hemoglobin need to be carried in red blood cells rather than directly in
vascular system? Hemoglobin is a large protein and has large surface area for a given
volume. This fact would increase the likelihood of water to get into the hemoglobin
molecule. Since water plays a key role in determining structure and regulating function of
proteins, it could change the shape of hemoglobin and also alter its functionality. Because
of the existence of other proteins outside the red blood cells, but within the vascular
system, as long as hemoglobin is in the RBC the osmotic pressure of the water is not
huge between inside and outside the red blood cell. In addition, the RBC membrane
regulates the water that comes into and out of the cell. Without this membrane, the
osmotic pressure in the vascular system could alter significantly and in addition,
hemoglobin molecules would be able to enter some organs, such as the liver, and
coagulate.
Hemoglobin is a tetramer and consists of four polypeptide chains, two called
alpha globin subunits, or α chains, and two called beta globin subunits, or β chains. The
alpha globin subunit is composed of 141 amino acids, whereas beta globin chain that
contains 146 amino acids. Both alpha and beta chains have very similar secondary and
tertiary structures, and fold into 8 α-helical segments, labeled helix A to G. Each globin
chain is bound to a non-protein group called heme, which in turn, is composed of a
porphyrin ring that contains carbon, nitrogen, and hydrogen atoms, with a single iron ion
( Fe 2 + ) at the center of the ring. The iron atom in collaboration with the rest of the heme
molecule is the portion of hemoglobin that gives the molecule oxygen-attracting
properties. The figure below illustrates the overall structure of a heme molecule:
Figure1. Structure of Heme molecule
If two heme molecules come together in the presence of oxygen, the iron ion
oxidized and as a result, binds to the oxygen irreversibly. Since oxygen needs to be
release in the tissues, this irreversible binding would not be useful in the hemoglobin.
This is why the globin chains in the hemoglobin are folded around the heme molecule:
They prevent this undesirable binding to take place by keeping heme molecules away
from each other. Therefore, even though the heme molecule is the core of oxygen binding
process, the globin chains play an important role to allow the iron atoms to bind just
loosely to the oxygen molecules in the lungs and then to release them into the tissues
without permanent oxidation of iron ions.
Since each hemoglobin molecule has four globins and four heme groups, it can
carry up to four molecules of oxygen. If we think about what happens to iron (and other
metals in general) when is exposed to the oxygen – for example, leaving it out in the air
for a while – the same chemical reaction takes place when oxygen binds to hemoglobin
molecule in the lungs: The color of the entire molecule turns red, because the oxygen
oxidizes the iron ion.
After inhalation, the partial pressure of oxygen – denoted as PO2 - is relatively
higher in the lungs (approximately 100 torr1) than in the tissues (can be as low as 20 torr).
Therefore, up to four oxygen molecules bind to each hemoglobin molecule, forming
oxyhemoglobin. In the lungs, the percentage of saturated oxygen binding sites in the
hemoglobin is high. The bloodstream transports the hemoglobin in the red blood cells to
the tissues, where the saturation level is relatively lower. The partial pressure difference
between lungs and tissues drives the unloading of oxygen from the hemoglobin to the
tissue through diffusion. The oxygen-hemoglobin dissociation curve plots the percentage
saturation of hemoglobin in red blood cells versus the partial pressure of oxygen PO2
level in the tissues in need of oxygen. The following figure illustrates that the oxygenhemoglobin dissociation curve is sigmoidal (S-shaped).
% changes rapidly
Figure2. Partial pressure of O2 in blood and tissues versus the percentage of binding
sites on hemoglobin that hold oxygen molecules.
1
Torr: A unit of pressure equal to that exerted by a column of mercury 1 mm high at 0°C and standard
gravity (1 mm Hg). Named after Evangelista Torricelli (1608–1647), inventor of the mercury barometer.
When an oxygen molecule binds to hemoglobin, a conformational change occurs
in the shape of hemoglobin, and makes it much more likely to bind oxygen. This
phenomenon is called cooperative binding. The importance of the sigmoidal curve is
that when the PO2 is in range between 25 and 50 mmHg, a relatively small change in
tissue partial pressure of oxygen results in a significant change in hemoglobin saturation.
For instance, when tissue PO2 changes from resting level at 40 mmHg to 30 mmHg, as
might be seen during exercise, the percentage saturation of hemoglobin drops drastically
from about 70% to about 30%. In other words, when the tissue is at rest, hemoglobin
release about 30% of the oxygen that is carrying and when the tissue needs more oxygen,
doing exercise for example, the hemoglobin gives up more oxygen and the oxygen
saturation levels drops to 30%. Without cooperative binding, all four hemoglobin
subunits would load and/or unload oxygen molecules at once, and as a result, the
dissociation curve would be linear instead of sigmoidal. Because of the sigmoidal
relationship characteristic of cooperative binding phenomenon, hemoglobin responds not
only quickly, but also effectively to small changes in oxygen demand.
Beside the partial pressure difference in oxygen-rich environment of the lungs and
the oxygen-poor environment of the tissues, there are other factors that contribute to the
ability of hemoglobin to release oxygen. Hemoglobin, like other proteins, is sensitive to
changes in PH and temperature. In addition, the partial pressure of carbon dioxide ( CO2
) can have a direct effect on hemoglobin. For instance, during exercise, CO2 produced
by exercising muscle reacts with the water that is present in blood as it is shown in the
following reaction:
CO2 + H 2 O → HCO3− + H +
As a result of this reaction, bicarbonate ion is produced and a hydrogen ion is
released, which in turn, decreases the level of PH in the tissue. i.e. the tissue becomes
more acidic than the lungs. Decreases in PH and increases in temperature result in
conformational change of hemoglobin, which implies more likelihood of hemoglobin to
release oxygen at a fixed value of tissue PO2 . This phenomenon is known as the Bohr
effect or Bohr shift. Bohr effect shifts the oxygen-hemoglobin dissociation curve to the
right and as a result, the amount of delivered O2 increases. Figure3 illustrates right and
left shift of the oxygen-hemoglobin dissociation curve.
www.unm.edu/~lkravitz/Medi
a/oxygencurve.jpg
Figure3. As PH drops, O2 becomes less likely to stay bound to hemoglobin
It is very important to remember that carbon dioxide as a waste is insoluble in
blood. On the contrary, bicarbonate ion is much soluble and can bind to hemoglobin to be
transported back to the lungs where the reverse reaction takes place. Consequently,
bicarbonate ion is converted back to carbon dioxide which then is exhaled by the lungs.
Therefore, the Bohr effect is crucial to removing carbon dioxide from the tissue beside
regulating oxygen delivery to the tissue in oxygen need. With the next inhalation, oxygen
is picked up again in the lungs and the cycle continues.
References:
Becker, Wayne, Lewis Kleinsmith, and Jeff Hardin. The World of the Cell. San Francisco: Benjamin
Cummings, 2002.
Berg, Jeremy, John Tymoczko, and Lubert Stryer. Biochemistry. W. H. Freeman, 2002.
Freeman, Scott. Biological Science. Upper Saddle River, NJ: Pearson Prentice Hall, 2005.
Perutz, M. F., Hemoglobin Structure and Respiratory Transport, Scientific American, volume 239,
number 6, December, 1978
Sears, Duane W. 1999. Overview of Hemoglobin's Structure/Function Relationships.
http://tutor.lscf.ucsb.edu/instdev/sears/biochemistry/tw-hbn/hba-overview.htm. February 2005.