Hemoglobin is an important factor in everyday life.

It is the protein that carries

oxygen from the lungs to the tissues and carries carbon dioxide from the tissues back to
the lungs. Its synthesis requires the production of both heme and globin. Hemoglobin is
made up of 4 proteins and a ‘heme’ group that contains iron. Heme is the group that
mediates reversible binding of oxygen by hemoglobin and globin is the protein that
surrounds the heme molecule, protecting it. The protein is formed by the combination of
two globin chains. One chain, alpha is found in every form of hemoglobin. The type of
other chain varies whether the hemoglobin is found in adults or in a fetus. It is
designated ‘non-alpha’ because of its changing characteristic.

One alpha chain paired to one non-alpha chain produces a hemoglobin dimer. In
order to efficiently deliver oxygen, two dimers must combine to form a hemoglobin
tetramer, the functional form of hemoglobin. The strength of the hemoglobin tetramer is
due to the bonding between the dimer pairs. This tetramer successfully controls the
uptake of oxygen in the lungs and the release of oxygen in the tissues. Hemoglobin is
defined by the way its individual subunits bind to one another first as a dimer and then as
a tetramer. The subunit interactions are also important because as they bind to one
another they in turn control the binding of allosteric regulatory molecules to the sites
they’ve created. The interactions in hemoglobin cause transitions between its tetrameric
oxy, or R for relaxed, and its deoxy, or T for tense. Transition between these
conformational states results in changes in the tertiary structure and changes the affinity
for oxygen to bind to the molecule. Certain sites in hemoglobin bind to 2,3-
diphosphoglycerate, protons, and chloride which change the hemoglobin to the R state
and result in the release of oxygen. The strengths of these interactions between allosteric
molecules and the molecule influence whether oxygen is released or bound.

These figures depict the difference in fetal and adult hemoglobins. The differences would be difficult to
visualize if not for the color-coding. On the left the fetal hemoglobin’s gamma chain is shown in blue, its
alpha chain is shown in red, its heme groups are a globular red, and its iron in green. On the right the
adult oxy hemoglobin is shown, its beta chain colored in green, its alpha chain is in red, its heme groups
are the globular red parts, and the irons are blue. These figures were created using RasMol Version 2.7 by
Herbert Bernstein and the molecule coordinates from the pdb file 1FDH created September 30, 1983 by
J.A. Frier, Jr. and the pdb file 1HHO created January 31, 1984 by B. Shaanan.
 Adult hemoglobin, “hemoglobin A” is formed from two alpha chains and two beta
chains, while fetal hemoglobin, “hemoglobin F” is formed from the combination of two
alpha chains and two gamma chains. This hemoglobin F is the primary hemoglobin in
the developing fetus. Hemoglobin F differs from hemoglobin A in the way its
interactions between dimer pairs alpha and gamma differ from the interactions between
alpha and beta. It also has a decreased 2,3-diphosphoglycerate response compared to
hemoglobin A. The tetramer-dimer interactions are much stronger in fetal hemoglobin,
which are thought to be involved in the efficient transfer of oxygen from the mother to
the fetus.

Fetal hemoglobin is the main hemoglobin that transports oxygen around the body
of the developing baby during the last six months of pregnancy. Its oxygen-binding
characteristics determine that it is best suited to the conditions in the womb and the
oxygen transport needs of babies still in their mothers’ wombs. Since a fetus is not
breathing on its own its hemoglobin has to be equipped with strong oxygen-binding
affinities. Towards the end of the gestational period the production of the gamma globin
declines while the production of the beta globin increases. Hemoglobin A becomes the
predominate hemoglobin within 12 to 16 weeks of birth. After birth babies automatically
turn off the production of fetal hemoglobin and turn on the production of adult
hemoglobin. This change is known as the ‘hemoglobin switch’. The entire process of
ridding ones body of fetal hemoglobin takes about two years. Some fetal hemoglobin
remains in the bloodstream for seven to eight months after birth but adults have trace
amounts or none at all by the time they reach adulthood.

Alternatively, this is a model of a deoxy human adult hemoglobin. Its heme group is shown in green, its
histeine groups are shown in orange, its beta chain is shown in blue, and its alpha chain is shown in red.
This figure was created using RasMol Version 2.7 by Herbert Bernstein and the molecule coordinates from
the pdb file 1A3N created April 29, 1998 by J. Tame and B. Vallone.

In adult hemoglobin, 20 ml of oxygen is transported for each 100 ml of blood and

the P50, or P02 at which hemoglobin is 50% saturated, is 26.7 mmHg. Fetal hemoglobin
has a P50 of 19 mmHg, which allows it to bind oxygen with more strength. At birth fetal
hemoglobin makes up 53-95% of total hemoglobin and at six months the number drops to
5%.
 A fetus is able to receive adequate oxygenation due to three factors: the presence
of fetal hemoglobin, the hemoglobin concentration being 50% greater in the body than in
the mother, and the Bohr effect. The Bohr effect explains that blood entering the placenta
on the baby’s side has a high concentration of carbon dioxide, which reaches equilibrium
with the mother’s blood rapidly. While the mother receives more carbon dioxide she
releases more oxygen and as the baby releases more carbon dioxide he binds more
oxygen, which favors the transport of oxygen from mother to fetus.

Through studying different types of hemoglobin we are able to understand the

effect different subunit interactions have on the way the heme proteins carry oxygen. The
knowledge gained from comparing fetal and adult hemoglobins can only benefit us in
solving the mystery of life.
References:

“Hemoglobin Synthesis” Joint Center for Sickle Cell and Thalassemic Disorders
January 9, 2001 http://sickle.bwh.harvard.edu/hbsynthesis.html (23 January
2001).

Dumoulin, A, Li, X., Manning, J., and Manning, L. “Normal and Abnormal Protein
Subunit Interactions in Hemoglobins” The Journal of Biological Chemistry Vol.
273, No. 31, July 31, 1998 http://www.jbc.org (23 January 2001).

“Fetal Hemoglobin (Hemoglobin F) Fact Sheet” Maryland Community and Public

Health Administration 2001
http://mdpublichealth.org/genetics/html/hemo_f.html (23 January 2001).

Voth, B. “Fetal vs. Adult Hemoglobin B Voth” University of Wisconsin Anesthesia

Topics 1993-1994
http://www.anesthesia.wisc.edu/Topics/Pediatric_Anesthesia/ftlvsadult.html
(23 January 2001).