Haemoglobin its structure, functions, types and abnormalities Prepared by :- Bhupinder Chayan Vermani Ayush Gupta Dibya shree

Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of vertebrates. Hemoglobin transports oxygen from the lungs or gills to the rest of the body, such as to the muscles, where it releases the oxygen for cell use. It also has a variety of other roles of gas transport and effect-modulation which vary from species to species, and are quite diverse in some invertebrates. Haemoglobin contains a haem group that has an iron atom at its centre. When the iron is bound to oxygen, the haem group is red in colour (oxyhameoglobin), and when it lacks oxygen (deoxygenated form) it is blue-red. SYNTHESIS :- Hemoglobin (Hb) is synthesized in a complex series of steps. The heme part is synthesized in a series of steps in the mitochondria and the cytosol of immature red blood cells, while the globin protein parts are synthesized by ribosomes in the cytosol. Production of Hb continues in the cell throughout its early development from the proerythroblast to the reticulocyte.

Structure Haemoglobin molecule is an assembly of four globular protein subunits. Each subunit is composed of a protein chain tightly associated with a non-protein heme group. Each protein chain arranges into a set of alpha-helix , structural segments connected together in a globin fold arrangement. This folding pattern contains a pocket which strongly binds the heme group. A heme group consists of an iron (Fe) ion (charged atom) held in a heterocyclic ring, known as a porphyrin. The iron ion, which is the site of oxygen binding, coordinates with the four nitrogens in the center of the ring, which all lie in one plane. The iron is also bound strongly to the globular protein via the imidazole ring of the histidine residue below the porphyrin ring. A sixth position can reversibly bind oxygen, completing the octahedral group of six ligands.

In adult humans, the most common hemoglobin type is a tetramer (which contains 4 subunit proteins) called hemoglobin A, consisting of two α and two β subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as α2β2. Hemoglobin A is the most intensively studied of the hemoglobin molecule. The four polypeptide chains are bound to each other by salt bridges, hydrogen bonds, and hydrophobic interactions. There are two kinds of contacts between the α and β chains: α1β1 and α2β2.

HbF : The predominant form of hemoglobin in a fetus and a newborn. Hemoglobin F is an immature form of Hb is composed of 2 α and 2 γ chains. Its life span is about 2 weeks. It has more affinity towards o2 than HbA. This is due to the fact that it does not interact with 2,3,-DPG (it lowers the o2 binding capacity of haemoglobin). It is less resistant to alkali denaturation. HbA2 : Hemoglobin A2 is a normal variant of hemoglobin A that consists of two alpha and two delta chains and is found in small quantity in normal human blood.

Methemoglobin it is a form of hemoglobin, in which the iron in the heme group is in the Fe3+ state, not the Fe2+ of normal hemoglobin. Methemoglobin cannot carry oxygen. Hemoglobin S (a2bs2) A variant form of hemoglobin found in people with sickle cell anemia. There is a variation in the β-chain gene, causing a change in the properties of hemoblobin which results in sickling of red blood cells.

Binding of o2 to Hb : OXYGENATION The oxygen molecule binds to Hb as a neutral ligand(ligand binding) and hence the process is known as oxygenation and not oxidation as the oxidation state of Fe remains +2. When oxygen binds to the iron center, it causes contraction of the iron atom, and causes it to move back into the center of the porphyrin ring plane . At the same time, the porphyrin ring plane itself is pushed away from the oxygen and toward the imidizole side chain of the histidine residue interacting at the other pole of the iron. This causes a tug on the peptide strand which tends to open up heme units in the remainder of the molecule, so that there is more room for oxygen molecules to bind at their heme sites.

Hence, when one subunit protein in hemoglobin becomes oxygenated, this induces a conformational or structural change in the whole complex, causing the other subunits to gain an increased affinity for oxygen. As a consequence, the oxygen binding curve of hemoglobin is sigmoidal, or S-shaped, as opposed to the normal hyperbolic curve associated with noncooperative binding.

Binding and release of ligands induces a conformational (structural) change in hemoglobin. Here, the binding and release of oxygen illustrates the structural differences between oxy- and deoxyhemoglobin, respectively. Only one of the four heme groups is shown.

Role in disease Decrease of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of anemia. As absence of iron decreases heme synthesis, red blood cells in iron deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic (smaller than normal). Sickle Cell Anemia: Sickle cell anemia, also known as sickle cell disease, is caused by a point mutation in the b globin gene. As a result of this mutation, valine is inserted into the 6th position in the b globin chain instead of glutamic acid . The hemoglobin sticks together when it delivers oxygen to the body’s tissues. These clumps of hemoglobin are like liquid fibers. They cause the red blood cells to become stiff and shaped like a sickle. Thalassemia: it is an inherited autosomal recessive blood disease. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin. Reduced synthesis of one of the globin chains can cause the formation of abnormal hemoglobin molecules, and this in turn causes the anemia which is the characteristic presenting symptom of the thalassemias.