Download Hemoglobin Hb

CHE 442: Proteins
Arwa Almejbel
Hemoglobin Hb
The hemoglobin protein is one of the most important proteins in our body as it is responsible
for the binding and transport of oxygen in the blood. Various scientists in the 1800s began to slowly
discover the properties of the protein, its interaction with heme and its presence in blood cells.
However, one of the major strides in hemoglobin research occurred via the work of Drs. Linus Pauling
and Charles Coryell, who discovered how oxygen binds to the heme molecule [2]. From their work, it
was determined that hemoglobin reversibly binds to oxygen, which can be transferred from one area
of the body to other locations.
The overall structure of the hemoglobin molecule is a quarternary structure results from the
association of two polypeptide chains [1]. However, the different subunits that comprise the molecule,
known as globins, are the primary polypeptide structures, or amino acid sequences, that form the
building blocks of the protein. Each globin in turn is bound to a heme group, which is what reversibly
binds to oxygen. In short, hemoglobin is comprised of four of globins, two alpha-globins (141 amino
acids each) and two beta-globins (146 amino acids each), with four heme groups. These four
subunits undergo non -covalent interactions to hold the structure together. The globins fold into
secondary and tertiary structures. The secondary structure of hemoglobin has only alpha helices for
each subunit ( 8-9 helices ) and no beta sheets. When the secondary and tertiary structure combined
form the overall quarternary structure of the protein [3]. The presence of the iron atom (Fe) at the
center of the circular heme molecule, known as porphyrin, is what allows oxygen to have an affinity
for each structure. Therefore, for every hemoglobin molecule in the body, four oxygen molecules can
bind to it. The proximal His58 interact with Fe ion above the plane of porphyrin. When oxygen binds,
the Fe+2 ion becomes Fe+3 with coordinate 6 and the iron atom moves into the plane of the porphyrin,
which flatten the porphyrin. Then shifts the location of the entire protein chain. These changes are
transmitted throughout the protein, ultimately causing the big shift in shape that changes the binding
strength of the neighboring sites.
Once oxygen is bound, the color of the metal becomes red looking and is known as
oxyhemoglobin (R form). If oxygen is not bound, also known as deoxyhemoglobin (T form), the color
of the metal is bluish-purple. The deoxy or T form is stabilized by 8 salt bridges, which are broken in
the transition to the oxy or R state. In addition, crucial H-bonds between Tyr 140 (alpha chain) or 145
(on the beta chain) and the carbonyl O of Val 93 (alpha chain) or 98 (beta chain) are broken. Not only
is hemoglobin important in the transport of oxygen in the body, but the transport of carbon dioxide.
This other important function of hemoglobin allows aid in the prevention of changes of blood pH, also
known as the buffering of the blood [2]. Unlike oxygen’s affinity for the iron atom, carbon dioxide
binds to the protein chains of the globin subunits.
As it may well be assumed, the inability of the hemoglobin molecule to function properly, in
this case, transport oxygen to tissues in the body, can lead to a serious health risk. The autosomal
recessive inherited disease, sickle-cell anemia, is an example of what can happen when hemoglobin
is mutated. In this disease, a genetic mutation at the sixth amino acid sequence of the beta globin
takes place, where valine and not glutamate, is added. The phenotypic consequence of this mutation
is the lack of charge on the beta chain due to valine, instead of the overall negative net charge that
glutamate has. As shown by Dr. Pauling in another study using gel electrophoresis, normal
hemoglobin molecules (HbA) versus abnormal ones (HbS), traveled faster than the latter as a result
of this disparity in charge [4]. Due to this single mutation, hemoglobin molecules have a “sticky”
hydrophobic patch that interacts with other hemoglobin molecules in blood capillaries where the
levels of oxygen are at the lowest. Subsequently, the hemoglobin molecules aggregate into rods and
cause the red blood cells to deform into their “sickle” form. This leads to a cascade of catastrophe, as
the frail red blood cells rupture easily and lead to the clogging and rupture of capillaries that ends in
the destruction of tissues and organs in the long run. Other problems such as the failure of the body
to maintain a normal blood pH, due to the failure of hemoglobin’s normal distribution of carbon dioxide
in the body [4].
References
1. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., Walter, P. (2002) Molecular Biology
of the Cell. (Eds.), pp. 461, Garland Science, New York.
2. Campbell, N.A., Reece, J.B., Taylor, M.R., Simon, E.J. (2006) Biology Concepts and Connections
(Eds.) (5th Ed.) pp. 46-462, Pearson, San Francisco.
3. Rousseot, N., Jaenicke, E., Lamkemeyer, T., Harris, J.R., Pirow, R. (2006) Native and subunit
molecular mass and quarternary structure of the hemoglobin from the primitive branchiopod
crustacean Triops cancriformis. FEBS J 17, 4055-71.
4. Starr C., Taggart, R. (2001) Biology: The Unity and Diversity of Life (6th Ed.) pp. 183-227,
Brooks/Cole, Pacific Grove.
5. Liddington R, Derewenda Z, Dodson E, Hubbard R, Dodson G. (1992) High resolution crystal
structures and comparisons of T-state deoxyhaemoglobin and two liganded T-state haemoglobins:
T(alpha-oxy)haemoglobin and T(met)haemoglobin. J Mol Biol. 228(2)551-79. PDB ID: 1HGA
6. Paoli, M., Liddington, R., Tame, J., Wilkinson, A., Dodson, G. (1996) Crystal structure of T state
haemoglobin with oxygen bound at all four haems. J.Mol.Biol. 256-775. PDB ID: 1BBB
7. Schechter, A. N. (2008) Hemoglobin research and the origins of molecular medicine. Blood.112
(10).