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The Structure and Function of the Hemoglobin Molecule
Hemoglobin is a conjugated protein combined with a heme group responsible for carrying oxygen from lungs to body tissues and carbon dioxide from tissues to lungs. It is present in the erythrocytes, which are formed in the bone marrow, and gives the blood red color. Furthermore, it is estimated that each blood cell contains about 280 million hemoglobin molecules.
The structure and functions of the hemoglobin molecule have been studied by many scientists, the most prominent of whom was Max Perutz, who won a Noble Prize in 1962 for conducting a research on hemoglobin (2). Perutz was the first who introduced a three-dimensional structure of hemoglobin based on X-ray analysis.
Hemoglobin (often abbreviated as Hb) has a tetrameter structure consisting of four polypeptide chains (globins), two of which are α-chains composed of 141 amino acids, and two β-chains (or two γ- or δ-chains depending on the type of hemoglobin) composed of 146 amino acids (4). Each chain is connected to an iron-containing molecule called heme (or haem). The latter consists of a ringlike compound known as a porphyrin, which includes four pyrrole molecules cyclically linked together with an iron ion (Fe+2) in the centre. When breathing, oxygen (O2), which is found in the air that we inhale combine with the iron atom of the heme group. This process is called oxygenation. Additionaly, hemoglobin saturated with oxygen is called oxyhemoglobin. Whereas each hemoglobin molecule contains four hemes and, thus, four atoms of iron, one hemoglobin molecule can join and transport maximum of four oxygen molecules.
Oxyhemoglobin is transported with the bloodstream to body tissues that require oxygen to sustain their processes. When blood reaches body tissues, oxyhemoglobin loses weakly-bound molecules of O2, which are disjoined and replaced with two protons and two molecules of carbon dioxide (CO2). As a result, carbaminohemoglobin is formed, which travels back to the lungs where it is released through exhalation and is replaced with oxygen (2). In such a way, hemoglobin serves as the oxygen and carbon dioxide carrier in blood, saturating body tissues with oxygen and removing waste products for their functioning in lungs and kidneys. Moreover, hemoglobin is involved in regulation of acid-base balance.
Affinity of Oxygen Binding
CO2 and O2 bind to the hemoglobin molecule and replace each other during the process of blood circulation. The oxygen molecule is bound to an iron atom, whereas carbon dioxide connects N-terminal end of each of the polypeptide chains of hemoglobin (3). However, both types of binding are weak, reversible and unstable.
The ability of hemoglobin to take up oxygen molecules depends on several factors, namely the presence of oxygen (so-called oxygen pressure), pH, carbon dioxide and DPG (2,3-diphosphoglycerate). The major factor that influences oxygen affinity is oxygen pressure, which depends on the form of hemoglobin. There are two forms of hemoglobin: tense form and relaxed form. In tense form hemoglobin has low affinity for oxygen because all four subunits of hemoglobin are joined tightly by salt bonds, hydrogen bonds and Van der Waals forcs (3). By contrast, in relaxed state hemoglobin has greater oxygen affinity. Thus, O2 bound to the α-chain and alters the structure of hemoglobin by rupturing salt bonds of the four hemoglobin subunits and thus facilitates binding of O2 to these subunits (3). Transformation from tense to relaxed state occurs when the first oxygen molecule binds to the T-structure under the high oxygen pressure environment in the lungs.
Binding of the first oxygen facilitates binding of the next oxygen to the same molecule of hemoglobin. Oxygen affinity increases with each oxygen bound to hemoglobin. Thus, it is estimated that binding of the fourth oxygen molecule is approximately 300 times that of the first one (2). This process is referred as a cooperative oxygen binding or positive cooperativity.
The oxygen binding curve for hemoglobin is sigmoidal in shape, which indicates that oxygen binding affinity for the first molecule of O2 is very low, but the next molecule is bound with much higher affinity. It suggests that the binding of the first O2 molecule increases the affinity of hemoglobin for oxygen. As a result of positive cooperativity, hemoglobin can take up more oxygen molecules than uncooperative myoglobin.
Effect of Carbon Monoxide on Hemoglobin
Hemoglobin can also bind other molecules such as gaseous nitric oxide (NO) and carbon monoxide (CO). The former has a positive effect on the walls of blood vessels, causing them to relax thus reducing the blood pressure. By contrast, carbon monoxide has a detrimental influence on blood cells.
CO is a toxic gas without a smell or color that is produced after incomplete combustion of fuel containing carbon (coal, petrol, natural gas). Carbon monoxide readily combines with the heme group and replaces oxygen, forming stable bonds that are difficult to remove. As a result of such binding, an abnormal hemoglobin derivative called carboxyhemoglobin (COHb) appears. CO has 210 times greater affinity than oxygen. Moreover, selective binding of carbon monoxide affects reduces oxygen affinity, moving oxyhemoglobin shifts to the left. As a result, even small amount of CO in the air results in formation of large number of COHb. The latter blocks normal oxygen binding, reducing oxygen transporting capacity of blood, and thus causing suffocation of cells. Deoxygenation of blood has detrimental health effects, including headache and nausea (0,02% concentration of CO in the air), unconsciousness (0,1% concentration), asphyxiation, etc. (1). Additionally, continuous subjection to a large concentration of CO can provoke coma or even death. Moreover, carbon monoxide triggers conformational changes in the hemoglobin structure, which results in various hemoglobinopathies.
Abnormal Hemoglobin in Sickle Cell Anemia
Hemoglobin has different forms depending on the age and level of development. Each of them, however, contains four polypeptide subunits formed by two α-chains and two β, γ, or δ chains. These are synthesised from amino acids under genetic control. Therefore, mutations in the genes responsible for coding globin chains affect formation and functioning of hemoglobin (3). Hemoglobin, which is formed as a result of gene mutations is called abnormal hemoglobin, and this conditioon is referred to as hemoglobinopathy.
There are a number of hemoglobinopathies, namely thalassemia (hemoglobin synthesis disorder caused by lack or decreased synthesis of α- or β-globin chains), sickle anemia (genetic disorder caused by production of an abnormal hemoglobin), sickle cell trait (a state in which a person is a carrier of abnormal mutated β-globin gene received from one parent) (3). Although sickle cell trait does not have any physical manifestations, in about 1 in 10 individuals with sickle cell trait can develop a severe chronic anemia, which is also referred to as sickle cell anemia (4). The disease generally affects people of African origin. However, the mutation of sickle hemoglobin was discovered in Africa, the Indian subcontinent, the Mediterranean, Turkey, North and South America, the Caribbean, and the United Kingdom (2). Moreover, according to the WHO, the rate of hemoglobinopathies depends on the availability of resources for treatment.
Sickled hemoglobin (HbS) is produced due to mutations in the β-globin gene responsible for coding β-globin chain. This mutation results in the alteration of amino acid sequence, in particular, glutamic acid, which is present in the sixth position of β-chain while in the normal adult hemoglobin (HbA) is replaced with a valine residue (3).
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As a result of the replacement of acids residues, hydrophobic contact called ‘sticky patch’ is formed on the outer surface of the β-chain, reducing the solubility of deoxygenated HbS. Therefore, deoxygenated HbS molecules bind to each other, forming insoluble long tubular fiber. The latter deforms the erythrocytes into C-shape. Sickled blood cells lose water, become fragile, and have shorter lifespan than normal cells. Furthermore, their membranes rupture result in sickle cell anemia (3). Moreover, sickled cells cause obtrusion of small capillaries, interrupting the supply of oxygen and ultimately leading to anoxia (oxygen deprivation) and death of the cell.
Sickle cell anemia normally occurs in the tense form of hemoglobin: low pH, increased temperature, and decreased availability of oxygen. Moreover, there are other pathognomonic factors favoring sickle hemoglobin polymerization, which results in sickle cell anemia (2). The disease produces severe effects such as inflammation, coagulopathy, arterial obstruction, red cell membrane disruption, vaso-occlusion, involving endothelial activation, leukocyte, and red cell adhesion, hemoglobin polymerization, vessel occlusion, and tissue damage from necrosis. The risk of pulmonary hypertension, renal failure, bone necrosis and osteoporosis, brain injury, coagulopathy, red cell destruction, vessel obstruction, and the related effects of inflammation in patients with sickle cell disease increases with age (2).
Having examined the physical and chemical properties of the normal hemoglobin, and compared them with the sickle hemoglobin, it was discovered that abnormal hemoglobin in sickle cell anemia is caused by mutated β-globin chain. As a result of the distorted cell structure, hemoglobin can no longer perform its main function, namely carry oxygen to body tissues. It was also discovered that carbon monoxide reduces oxygen affinity of the hemoglobin molecule, thus resulting in serious negative health effects.
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