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The Mutation in Hemoglobin
Sickle cell disease is a blood condition seen most commonly in people of African ancestry and in the tribal peoples of India. Clinically significant sickle cell syndromes also occur in people of Mediterranean and Middle Eastern background. Here, the most common problem is a combination sickle cell and beta thalassemia genes. The sickle cell mutation reflects a single change in the amino acid building blocks of the oxygen-transport protein, hemoglobin. This protein, which is the component that gives red cells their color, has two subunits. The alpha subunit is normal in people with sickle cell disease. The beta subunit has the amino acid valine at position 6 instead of the glutamic acid that is normally present. The alteration is the basis of all the problems that occur in people with sickle cell disease. The schematic diagram shows the first eight of the 146 amino acids in the beta globin subunit of the hemoglobin molecule. The amino acids of the hemoglobin protein are represented as a series of linked, colored boxes. The lavender box represents the normal glutamic acid at position 6. The dark green box represents the valine in sickle cell hemoglobin. The other amino acids in sickle and normal hemoglobin are identical.
Schematic Represntation of the Amino Acid Substitution in Sickle Cell Disease

Figure 1. The chain of colored boxes represent the first eight amino acids in the beta chain of hemoglobin. The sixth position in the normal beta chain has glutamic acid, while sickle beta chain has valine. This is the sole difference between the two.
The molecule, DNA (deoxyribonucleic acid), is the fundamental genetic material that determines the arrangement of the amino acid building blocks in all proteins. Segments of DNA that code for particular proteins are called genes. The gene that controls the production of the beta globin subunit of hemoglobin is located on one of the 46 human chromosomes (chromosome #11). People have twenty-two identical chromosome pairs (the twenty-third pair is the unlike X and Y chromosomes that determine a person's sex). One of each pair is inherited from the father, and one from the mother. Occasionally, a gene is altered in the exchange between parent and offspring. This event, called mutation, occurs extremely rarely. Therefore, the inheritance of sickle cell disease depends totally on the genes of the parents.
If only one of the beta globin genes is the "sickle" gene and the other is normal, the person is a carrier for sickle cell disease. The condition is called sickle cell trait. With a few rare exceptions, people with sickle cell trait are completely normal. If both beta globin genes code for the sickle protein, the person has sickle cell disease. Sickle cell disease is determined at conception, when a person acquires his/her genes from the parents. Sickle cell disease cannot be caught, acquired, or otherwise transmitted. Also, sickle cell trait does not develop into sickle cell disease. Sickle cell trait partially protects people from the deadly consequences of malaria. The frequency of the sickle cell gene reached high levels in Africa and India due to the protection against malaria that occurred for people with sickle cell trait.
Oxygen and the Formation of Polymers of Sickle Hemoglobin

Figure 2. Normal hemglobin exists as solitary units whether oxygenated or deoxygenated (upper panel). In contrast, sickle hemoglobin molecules adhere when they are deoxygenated, forming sickle hemoglobin polymers (lower panel).
The hemoglobin molecule (made of alpha and beta globin subunits) picks up oxygen in the lungs and releases it when the red cells reach peripheral tissues, such as the muscles. Ordinarily, the hemoglobin molecules exist as single, isolated units in the red cell, whether they have oxygen bound or not. Normal red cells maintain a basic disc shape, whether they are transporting oxygen or not.
The picture is different with sickle hemoglobin (Figure 2). Sickle hemoglobin exists as isolated units in the red cells when they have oxygen bound. When sickle hemoglobin releases oxygen in the peripheral tissues, however, the molecules tend to stick together and form long chains or polymers. These rigid polymers distort the cell and cause it to bend out of shape. While most distorted cells are simply shaped irregularly, a few have a cresent-like appearence under the microscope. These cresent-like or "sickle shaped" red cells gave the disorder its name. When the red cells return to the lungs and pick up oxygen again, the hemoglobin molecules resume their solitary existence (the left of the diagram).
A single red cell may traverse the circulation four times in one minute. Sickle hemoglobin undergoes repeated episodes of polymerization and depolymerization. This cyclic alteration in the state of the molecules damages the hemoglobin and ultimately the red cell itself.
Polymerized sickle hemoglobin does not form single strands. Instead, the molecules group in long bundles of 14 strands each that twist in a regular fashion, much like a braid (Figure 3).
Schematic Representaion of Polymerized Sickle Hemoglobin

Figure 3. Polymers of deoxygenated sickle hemoglobin molecules. Each hemoglobin molecule is represented as a sphere. The spheres twist in an alpha helical bundle made of 14 sickle hemoglobin chains.
These bundles self-associate into even larger structures that stretch and distort the cell. An analogy would be a water balloon which was stretched and deformed by icicles. The stretching of the balloon's rubber is similar to what happens to the membrane of the red cell. Polymers tend to grow from a single start site (called a nucleation site) and often grow in multiple directions. Star-shaped clusters of hemoglobin S polmers develop commonly.
Despite their imposing appearance, the sickle hemoglobin polymers are held together by very weak forces. The abnormal valine amino acid at position 6 in the beta globin chain interacts weakly with the beta globin chain in an adjacent sickle hemoglobin molecule. The complex twisting, 14-strand structure of the bundles produces multiple interactions and cross-interactions between molecules. The weak nature of the interaction opens one strategy to treat sickle cell disease.
Some types of hemoglobin molecules, such as that found before birth (fetal hemoglobin), block the interactions between the deoxygenated hemoglobin S molecules. All people have fetal hemoglobin in their circulation before birth. Fetal hemoglobin protects the unborn child and newborns from the effects of sickle cell hemoglobin. Unfortunately, this hemoglobin disappears within the first year after birth. One approach to treating sickle cell disease is to rekindle production of fetal hemoglobin. The drug, hydroxyurea induces fetal hemoglobin production in some patients with sickle cell disease and improves the clinical condition of some people.

The Sickle Red Cell
Capillary Flow of Normal and Sickle Red Cells

Figure 4. Normal red cells maintain their shape as they pass through the capillaries and release oxygen to the peripheral tissues (upper panel). Hemoglobin polymers form in the sickle rell cells with oxygen release, causing them to deform. The deformed cells block the flow of cells and interrupt the delivery of oxygen to the tissues (lower panel).
Figure 4 shows the changes that occur as sickle or normal red cells release oxygen in the microcirculation. The upper panel shows that normal red cells retain their biconcave shape and move through the smallest vessels (capillaries) without problem. In contrast, the hemoglobin polymerizes in sickle red cells when they release oxygen, as shown in the lower panel. The polymerization of hemoglobin deforms the red cells. The problem, however, is not simply one of abnormal shape. The membranes of the cells are rigid due in part to repeated episodes of hemoglobin polymerization/depolymerization as the cells pick up and release oxygen in the circulation. These rigid cells fail to move through the small blood vessels, blocking local blood flow to a microscopic region of tissue. Amplified many times, these episodes produce tissue hypoxia (low oxygen supply). The result is pain, and often damage to organs.
The damage to red cell membranes promotes many of the complications of sickle cell disease. Robert Hebbel at the University of Minnesota and colleagues were among the first workers to show that the heme component of hemoglobin tends to be released from the protein with repeated episodes of sickle hemoglobin polymerization. Some of this free heme lodges in the red cell membrane. The iron in the center of the heme molecule promotes formation of very dangerous compounds, called reactive oxygen species. These molecules damage both the lipid and protein components of the red cell membrane. Membrane stiffness is one of the consequences of this injury. Also, the damaged proteins tend to clump together to form abnormal clusters in the red cell membrane. Antibodies develop to these protein clusters, leading to even more red cell destruction (hemolysis).
The anemia in sickle cell disease is caused by red cell destruction, or hemolysis. The production of red cells by the bone marrow increases dramatically, but is unable to keep pace with the destruction. Red cell production increases by five to ten-fold in most patients with sickle cell disease. The average half-life of normal red cells is about 40 days. In patients with sickle cell disease, this value can fall to as low as four days. The volume of "active" bone marrow is much greater than normal in patients with sickle cell disease due to the demand for greater red cell production.
The degree of anemia varies widely between patients. In general, patients with sickle cell disease have hematocrits that are roughly half the normal value (e.g., about 25% compared to about 40-45% normally). Patients with hemoglobin SC disease (where one of the beta globin genes codes for hemoglobin S and the other for the variant, hemoglobin C) have higher hematocrits than do those with homozygous Hb SS disease. The hematocrits of patients with Hb SC disease run in low- to mid-thirties. The hematocrit is normal for people with sickle cell trait.

The hemoglobin molecule is made up of four polypeptide chains (Alpha 1, Beta 1 , Alpha 2, Beta 2), noncovalently bound to each other. There are four heme-iron complexes.
Each chain holds a heme group containing one Fe++ atom.
The heme-iron complexes are colored red because they give hemoglobin its red color.
Now the heme molecules have been colored by element.
C H O N Fe
(Hydrogens are not resolved by x-ray crystallography, from which this structure was obtained.)
Spacefill view of atoms that make up a single heme molecule.
Here is how iron is attached to the rest of the heme molecule.
C H O N Fe
An elemental oxygen molecule binds to the ferrous iron atom in the lungs where oxygen is abundant, and is released later in tissues which need oxygen.
The position of bound elemental oxygen in one chain of hemoglobin.
Space occupied by the heme bound oxygen in the polypeptide chain.
The nitrogens in two histidines bind to the iron, anchoring its position. The hydrophilic propanoate groups of heme face the water at the surface of the protein, while the hydrophobic portions of the heme are buried among the hydrophobic amino acids of the protein.
A spacefill view (with the exception of the heme molecule) of the hemoglobin polypeptide chain.

Hemoglobin is contained within red blood cells also called Erythrocytes.
Erythrocytes compose approximately 45% of human blood volume (Vander 373). In each erythrocyte there are approximately 350 million hemoglobin molecules (Knowledge html). Hemoglobin molecules supply 98.5% of the oxygen to the cells of the body (Vander 482). Each hemoglobin molecule can carry four oxygen or carbon dioxide molecules.
What does a hemoglobin molecule look like? See also Structures of hemoglobin and myoglobin
A hemoglobin molecule is made up of four polypeptide chains and heme groups. And these chains are held together by noncovalent attractions (Stryer 154). The hemoglobin molecule is made up of two alpha chains and two beta chains. The alpha chains are in contact with each of the other two beta chains but have few interactions between themselves. The beta chains also have few interactions between themselves (Stryer 155).


In yellow is the alpha chain, in blue is the beta chain and in red is the heme. [ Image of hemoglobin from Stryer page 155 ]
Each heme group contains an iron atom (Fe). The iron atom is the part of the heme group that allows for oxygen binding and thus transport (Vander 482). When one of the four iron atom binds oxygen it causes a structural change, visible below, and this allow the other iron atoms to more easily bind oxygen (Stryer 153).


I. Introduction
Approximately one third of the mass of a mammalian red blood cell is hemoglobin. Its major function is to carry oxygen from the lungs through the arteries to the tissues and help to carry carbon dioxide through the veins back to the lungs. The process whereby hemoglobin performs this essential physiological role is characterized by a cooperative interaction among its constituent subunits. Hemoglobin has thus assumed the role of a model system whose study acquires ramifications extending far beyond its own function as an oxygen transport system.


II. Protein Structure
The hemoglobin molecule is made up of four polypeptide chains: two alpha chains < >of 141 amino acid residues each and two beta chains < > of 146 amino acid residues each. The alpha and beta chains have different sequences of amino acids, but fold up to form similar three-dimensional structures. The four chains are held together by noncovalent interactions. There are four binding sites for oxygen on the hemoglobin molecule, because each chain contains one heme group < >. In the alpha chain, the 87th residue is histidine F8 < >and in the beta chain the 92nd residue is histidine F8 >. A heme group is attached to each of the four histidines. The heme consists of an organic part and an iron atom < >. The iron atom in heme binds to the four nitrogens in the center of the protoporphyrin ring. The hemoglobin molecule is nearly spherical, with a diameter of 55 angstroms . The four chains are packed together to form a tetramer. The heme groups are located in crevices near the exterior of the molecule, one in each subunit. Each alpha chain is in contact with both beta chains< >. However, there are few interactions between the two alpha chains or between the two beta chains >.
Each polypeptide chain is made up of eight or nine alpha-helical segments < >and an equal number of nonhelical ones placed at the corners between them and at the ends of the chain. The helices are named A-H, starting from the amino acid terminus, and the nonhelical segments that lie between the helices are named AB, BC, CD, etc. The nonhelical segments at the ends of the chain are called NA at the amino terminus and HC at the carboxyl terminus.
To form the tetramer < >, each of the subunits is joined to its partner around a twofold symmetry axis, so that a rotation of 180 degrees brings one subunit into congruence with its partner. One pair of chains is then inverted and placed on top of the other pair so that the four chains lie at the corners of a tetrahedron. The four subunits are held together mainly by nonpolar interactions and hydrogen bonds. There are no covalent bonds between subunits. The twofold symmetry axis that relates the pairs of alpha and beta chains runs through a water-filled cavity >at the center of the molecule. This cavity widens upon transition form the R structure to the T structure to form a receptor site for the allosteric effector DPG (2,3 diphosphoglycerate) between the two beta chains. The heme group is wedged into a pocket of the globin with its hydrocarbon side chains interior and its polar propionate side chains exterior.
There are nine positions in the amino acid sequence that contain the same amino acid in all or nearly all species studied thus far. These conserved positions are especially important for the function of the hemoglobin molecule. Several of them, such as histidines F8 (His87)< > and E7 (His63)< >, are directly involved in the oxygen-binding site< > . Phenylalanine CD1 (Phe43) < > and leucine F4 (Leu83) < > are also in direct contact with the heme group< >. Tyrosine HC2 (Tyr140) < >stabilizes the molecule by forming a hydrogen bond between the H< > and F helices< >. Glycine B6 (Gly25)< >is conserved because of its small size: a side chain larger than a hydrogen atom would not allow theB< > and E helices< > to approach each other as closely as they do. Proline C2 (Pro37)< > is important because it terminates the C helix. Threonine C4 (Thr39) and lysine H10 (Lys127) are also conserved residues, but their roles are uncertain.


III. Transition from the T Structure to the R Structure
There are two kinds of contact regions between the alpha and beta chains: the alpha1beta1 and the alpha1beta2 contacts. Upon transmission from the deoxy (T) structure to the oxy (R) structure, the alpha1beta2 dimer rotates relative to the other by 15 degrees. Some atoms at this interface shift by as much as 6 angstroms . The alpha1beta2 contact region is designed to act as a switch between two alternative structures. The T structure is constrained by additional bonds between the subunits, which oppose the changes in tertiary structure needed to flatten the hemes upon combination with oxygen. These bonds take the form of salt bridges.
Transition from the T structure< > to the R structure< > is triggered by stereochemical changes at the hemes. In deoxyhemoglobin, the iron atom is about 0.6 angstroms out of the heme plane because of steric repulsion between the proximal histidine and the nitrogen atoms of the porphyrin. The heme group and proximal histidine make intimate contact with some fifteen side chains and so the structures of the F helix, the EF corner, and the FG corner change on oxygenation. These changes are then transmitted to the subunit interfaces. The expulsion of the tyrosine HC2 from the pocket between the F and H helices leads to the rupture of interchain salt bridges. Consequently, the equilibrium between the two quaternary structures is shifted to the R form on oxygenation.


IV. Cooperative Binding of Oxygen
The binding of oxygen to the heme group of one subunit has the effect of increasing the affinity of a neighboring subunit (on the same molecule) for oxygen< >. Deoxyhemoglobin is a taut moleucule, contrained by its eight salt links between the four subunits. Oxygenation cannot occur unless some of these salt links are broken so that the iron atom can move into the plane of the heme group. The number of salt links that need to be broken for the binding of an oxygen molecule depends on whether it is the first, second, third, or fourth to be bound. More salt links must be broken to permit the entry of the first oxygen molecule than of subsequent ones. Because energy is required to break salt links, the binding of the first oxygen molecule is energetically less favorable than that of subsequent oxygen molecules.