Hemoglobin Synthesis

Formation of Hemoglobin

Synthesis of hemoglobin begins in the pro-erythroblasts and continues even into the reticulocyte stage of the red blood cells. However, hemoglobin appears in the intermediate noroblastic stage.Therefore, when reticulocytes leave the bone marrow and pass into the blood stream, they continue to form minute quantities of hemoglobin for another day or so until they become mature erythrocytes.

Heme portion of the hemoglobin is synthesized in mitochondria and the globin part is synthesized in ribosomes. 

The basic chemical steps in the formation of hemoglobin. 

First, succinyl-CoA, formed in the Krebs metabolic cycle, binds with glycine to form a pyrrole molecule. 

In turn, four pyrroles combine to form protoporphyrin IX, which then combines with iron to form the heme molecule. 

Finally, each heme molecule combines with a long polypeptide chain, a globin synthesized by ribosomes, forming a subunit of hemoglobin called a hemoglobin chain. 

 

Each chain has a molecular weight of about 16,000; four of these in turn bind together loosely to form the whole hemoglobin molecule.

HEME SYNTHESIS

Heme is synthesized from succinyl-CoA and the glycine. 

Step – 1: It occurs in mitochondrion. Two molecules of Succinyl – CoA combines with two molecules of glycine and condense to form 5-aminolevulic acid (ALA) by ALA synthase.

ALA is transported to the cytoplasm. Two molecules of ALA combines to form Porphobilinogen in the presence of ALA Dehydratase. 

Porphobilinogen is converted into uroporphobilinogen I by uroporphobilinogen synthase.

Uroporphobilinogen I is converted into uroporphobilinogen III by porphobilinogen III Cosynthase.

From uroporphobilinogen III, a ring structure called coprophorphyrinogen IIIis formed by uroporphobilinogen decarboxylase.

Coprpporphyrinogen III is transported back to the mitochondrion, where it is oxidized to form protoporphyrinogen IX by corproporphyrinogen oxidase.

Protoporphyrinogen IX is converted into protoporphyrin IX by protoporphyrinogen oxidase.

Protoporphyrin IX combines with iron to form heme in the presence of ferrochelatase.

Formation of Globin

Polypeptide chains of globin are produced in the ribosomes. There are four types of polypeptide chains namely, alpha, beta, gamma and delta chains.

Each globin molecules is formed by the combination of 2 pairs of chains and each chain is made of 141 to 146 amino acids.

Adult Hb contains two alpha chains and two beta chains.

Fetal hemoglobin contains two alpha chains and two gamma chains.

Each polypeptide chains combines with one heme molecules. Thus after the complete configuration, each hemoglobin molecules contains 4 polypeptide chains and 4 heme molecules.

 

 

There are several slight variations in the different sub-unit hemoglobin chains, depending on the amino acid composition of the polypeptide portion. The different types of chains are designated alpha chains, beta chains, gamma chains, and delta chains. The most common form of hemoglobin in the adult human being, hemoglobin A, is a combination of two alpha chains and two beta chains.Hemoglobin A has a molecular weight of 64,458.


Because each hemoglobin chain has a heme prosthetic group containing an atom of iron, and because there are four hemoglobin chains in each hemoglobin molecule, one finds four iron atoms in each hemoglobin molecule; each of these can bind loosely with one molecule of oxygen, making a total of four molecules of oxygen (or eight oxygen atoms) that can be trans-ported by each hemoglobin molecule.

The types of hemoglobin chains in the hemoglobin molecule determine the binding affinity of the hemoglobin for oxygen. Abnormalities of the chains can alter the physical characteristics of the hemoglobin molecule as well. For instance, in sickle cell anemia, the amino acid valine is substituted for glutamic acid at one point in each of the two beta chains.

When this type of hemoglobin is exposed to low oxygen, it forms elongated crystals inside the red blood cells that are sometimes 15 micrometers in length. These make it almost impossible for the cells to pass through many small capillaries, and the spiked ends of the crystals are likely to rupture the cell membranes, leading to sickle cell anemia.

Combination of Hemoglobin with Oxygen. The most important feature of the hemoglobin molecule is its ability to combine loosely and reversibly with oxygen. This ability is discussed in detail in relation to respiration, because the primary function of hemoglobin in the body is to combine with oxygen in the lungs and then to release this oxygen readily in the peripheral tissue capillaries, where the gaseous tension of oxygen is much lower than in the lungs.

Oxygen does not combine with the two positive bonds of the iron in the hemoglobin molecule. Instead, it binds loosely with one of the so-called coordination bonds of the iron atom. This is an extremely loose bond, so that the combination is easily reversible. Further more, the oxygen does not become ionic oxygen but is carried as molecular oxygen (composed of two oxygen atoms) to the tissues, where, because of the loose, readily reversible combination, it is released into the tissue fluids still in the form of molecular oxygen rather than ionic oxygen.

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https://www.slideshare.net/nileshkate79/haemoglobin-58248275 

https://www.slideshare.net/mhnsathish/hemoglobin-synthesis-93914017 

 https://www.brainkart.com/article/Formation-of-Hemoglobin_19490/

 

 

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