Biology

Structure
Hemoglobin is a protein that is found in the red blood cells. The hemoglobin molecule has a tetramer structure made up of four polypeptide chains two beta globins and two alpha globins. The alpha globin chain has 141 amino acids while the beta globin chain is made up of 146 amino acids (Nabili, n.d). The tertiary and secondary structures of alpha and beta globin proteins are very similar, each having eight helical segments. Moreover, one heme molecule is found in every globin chain, and this molecule has a porphyrin ring with four pyrrole molecules linked together cyclically, and bound in the center by an iron ion.

The heme molecule is situated amid helix E and F of the globin protein. The globin chains have subunits of alpha and beta exist which are present in two dimmers attached together tightly. Hemoglobin has amino acids that make alpha helices, joined together by small non helical segments. The helical segments in the protein are stabilized by hydrogen, making them to pull towards each other inside the molecule, and every polypeptide chain folds into a particular shape. The quaternary structure of the hemoglobin forms a tetrahedral figure of four subunits (Natzke, 1998). The folding pattern is made up of a pocket that bonds the heme group strongly.

A matured person has a type of hemoglobin that is tetramer with four subunits of protein known as hemoglobin A. Each sub-unit has similar structures and sizes that are almost equal, and a molecular weight of close to 17,000 daltons. The hemoglobin molecule of an infant contains two gamma and two alpha chains and as the baby gets older, the gamma chains are slowly replaced by the beta chains. Lastly, the chains of the four polypeptides are closely held together by salt bridges, hydrophobic interactions, and hydrogen bond.

Functions
The basic role of hemoglobin is to carry oxygen from the lungs to the rest of the body tissues and then carry carbon dioxide back to the lungs from the body tissues. A single molecule of hemoglobin can carry up to four molecules of oxygen. Oxyhemoglobin is a form of hemoglobin that is saturated with oxygen and the one desaturated with oxygen is known as deoxyhemoglobin (Hsia, 2001). In the lungs, oxygen binds on the oxyhemoglobin and is supplied to the tissues through the blood steam. In the tissues, oxygen binds to myoglobin which is then carried to the mitochondria where it is consequently used for respiration. On the other hand, deoxyhemoglobin carries two molecules and two protons of carbon dioxide to the lungs which then releases it through exhalation.

Hemoglobins ability to receive oxygen molecules from the lungs and later release them in the body is controlled by factors inside the hemoglobin molecule and chemical factors that are external. A major regulator of the ability of hemoglobin to acquire oxygen is the quantity of oxygen itself that is available. After oxyhemoglobin manages to bind a single oxygen molecule, its affinity for more oxygen goes up until its saturated (Midline Plus, n.d). When an oxygen molecule is lost by deoxyhemoglobin, its affinity for oxygen that is remaining is diminished. This kind of regulation is called cooperativity and is crucial for the functions of the hemoglobin since it enables the oxyhemoglobin to transport enough amounts of oxygen to the body tissues, and deoxyhemoglobin to release all the oxygen molecules into the tissues.

Unique structural characteristics of hemoglobin enable the functioning of cooperativity and studies have revealed that the cooperative characteristic is lost when hemoglobin is divided into half. In essence, hemoglobin appears to be an allosetric protein which acquires many shapes and its structure can go through conformational changes depending on environmental conditions. Two different structures that hemoglobin can take include the relaxed structure (R) and the tense structure (T). The R structure has a higher affinity for oxygen while the T structure has a lower affinity for oxygen. The shift from T to R structures depends on the presence or absence of oxygen. Moreover, the ability of hemoglobin to acquire oxygen is controlled by chemical factors that are external such as pH, CO2, and DPG (2,3-diphosphoglycerate) ( HYPERLINK httpBio.davidson.edu t _blank Bio.davidson.edu, 2006).

The Bohr Effect
The pH found in the tissues is lower meaning that it is more acidic than the one in the lungs. Protons are formed when carbon dioxide and water reacts and this results to bicarbonate. There are two functions for increased acidity. First, protons reduce hemoglobins affinity for oxygen, thus enabling it to be easily released in the tissues. In the process of releasing the four molecules into the tissues, two protons are bound by hemoglobin. This is referred to as the Bohr Effect where equilibrium is maintained which is important for the release of CO2 as waste since it cannot dissolve in the blood stream. The bicarbonates ions can dissolve and be carried back to the lungs after hemoglobin binds it (USA Today, 2008). If the excess protons are not absorbed by the hemoglobin, it will become impossible to remove carbon dioxide.

Mutation of hemoglobin
The mutations that occur due to the hemoglobin dysfunction comes as a process that involves the messenger RNA precursor, then it follows that the post-transcriptional processing with methylation, translation, that proceeds through three different phases of initiation, elongation and termination. After all this, there is finally the interaction of the hemoglobin chains that form mature chains. Generally, these mutations that are as a result of hemoglobin disorders are either those consisting of the structural abnormalities and from the reduced globin synthesis.

Those that result from the abnormalities of hemoglobin structure are for example sickle cell anemia. The carriers are generally healthy though they can develop certain problems when in conditions of low oxygen saturation such as deep sea diving or during general anesthesia. The sickle cell mutation involves the change of base of A to T in the second nucleotide of the sixth codon in the beta-globin gene that results in the substitution of the valine for the glutamic acids such as the GTG and GAG. This eventually leads to the formation of a tetramer that is usually unstable in the deoxygenated form. If this continues and the saturation of oxygen goes below 85 percent, then the tetramers form some rod-like structures that cause the red blood cells to become sickle cell (Medline Plus, n.d). The effect of this is the resulting of hemolytic anemia that is being caused by the sickled red cell being fragile and also the occlusion of the peripheral circulation as a result of the clumping together of these cells.

Another mutation is called the alpha-thelassaemia that is being caused by the deficiency of the alpha-globin chain synthesis. Here, the processes involved are the deletion of one or both the contiguous alpha-globin genes being as a result of the unequal crossing over of the homologous sequences of the alpha-globin gene cluster. The individuals that are having this problem are usually asymptomatic with a mild anaemia and hemoglobin levels that are ten to twenty grammes per hundred milliliters (Natzke, 1998). All this leads to the erythropoiesis and increased red cell destruction and finally causes severe hemolytic anemia which leads to the expansion of the bone marrow cavities that finally cause bone deformity and the risk of the pathological fracture.

As a result of these gene frequencies that are definitely high and that have different forms of haemoglobinopathy in the area of high malaria infections, the individuals that are there will have to inherit the alpha andor beta-globin gene clusters. This is by the way of many observations made consistently.

The sickling variety of the hemoglobin gene is related to missense mutation. The molecular disease called sickle cell anemia occurs after mutation alters one area in the amino acid sequence of hemoglobin (Hb) molecule. People who inherit two mutant copies of the beta globin gene suffer from this disease. Linus Pauling a Nobel Laureate (1940s), and Verne Ingram (1950s) showed that the mutation was a result of transversion from thymine to adenine. This leads to the conversion of an amino acid which is close to the end of the beta chain of a persons hemoglobin, from glutamic acid side to a valine.

The hydrophilic side chain which is negatively charged is changed to a hydrophobic side chain leading to the conversion of HbA to HbS. When this occurs, the way in which hemoglobin molecules cumulate at low concentration of oxygen is altered, and the HbS molecules make the red blood cells containing hemoglobin to bend and form a sickle shape. Moreover, sickle cell hemoglobin molecules stick together and form rigid rods which are unable to transport oxygen well, leading to clogged capillaries that cut off blood supply to sensitive tissues like the brain and the heart. The sick individual goes through terrible pain and a possible heart attack or stroke can occur, just because of one nucleotide mutation.

Hemoglobin and sickle cell anemia- Malaria-
There is a greater incidence of the sickle cell malaria and malaria it is often believed that sickle cell provides resistance for malaria. First malaria is being caused by the plasmodium parasite whose life cycle is in the human beings red blood cells, after this the blood cells with the sickle-cell trait break down after infection. The red blood cells that have the trait of sickle cell tend to have low oxygen tension. This parasite reduces the oxygen tension in the blood cells that they infect because they use oxygen for their own metabolism. On the other hand in the case of low oxygen levels the potassium in the red blood cells leak out to be used by the parasite due to the for its development. Therefore, the resistance of the individuals with sickle cell trait to malaria is explained by the increase in immunity. These individuals in the malaria epidemic areas get the parasite of malaria that is introduced in their bloodstreams during their childhood. Because of this association of the individual body with the parasite then the carriers get the immunity against malaria.

Sickle cell anemia results from a mutation in the Hbs gene. Humans have two copies of the gene that code for the normal hemoglobin protein. Mutation in both copies of the gene result in errors in the transcription of hemoglobin protein which result in abnormal mutant hemoglobin. This abnormal form of hemoglobin causes the erythrocytes of the victims of the disease to lose their oxygen and fold into a sickle abnormal shape during intense activity. This results in the interference in their flow in blood vessels causing manifestation of the symptoms of the diseases in form of pain, swelling and tissue damage which can be lethal. Mutation in one copy of the gene does not result in the complete diseases and victims are called carriers and suffer less severe symptoms. Researchers have revealed that mutation in this gene grants resistance to malaria especially in areas that are hit by malaria like the tropics where 40 of population has at least one mutant copy of the Hbs gene. This shows that the mutant gene has naturally selected to confer resistance to malaria in these regions. The erythrocytes of the victims of this disease fold into their sickle abnormal shape when they are infected by the malaria protozoan parasite. This abnormal shape makes them to be filtered out of the bloodstream by the spleen as it passes through due to their shape. Therefore, the parasite is eradicated together with the abnormal red blood cell. This lethal mutation in the Hbs gene that cause sickle cell anemia is an example of mutations that are sometimes beneficial because it confers a survival benefit against malaria