Gene clusters of different chains of haemoglobin
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Explanation:
Hemoglobin synthesis requires the coordinated production of heme and globin. Heme is the prosthetic group that mediates reversible binding of oxygen by hemoglobin. Globin is the protein that surrounds and protects the heme molecule.
Heme Synthesis
Heme is synthesized in a complex series of steps involving enzymes in the mitochondrion and in the cytosol of the cell (Figure 1). The first step in heme synthesis takes place in the mitochondrion, with the condensation of succinyl CoA and glycine by ALA synthase to form 5-aminolevulic acid (ALA). This molecule is transported to the cytosol where a series of reactions produce a ring structure called coproporphyrinogen III. This molecule returns to the mitochondrion where an addition reaction produces protoporhyrin IX.
Heme Biosynthesis
Mitochondrial Biosynthesis of Heme
Figure 1 Heme Biosynthesis.
The sythesis of heme is a complex process that involves multiple enzymatic steps. The process begins in the mitochondrion with the condensation of succinyl-CoA and glycine to form 5-aminolevulinic acid. A series of steps in the cytoplasm produce coproporphrynogen III, which re-enters the mitochondrion. The final enzymatic steps produce heme.The enzyme ferrochelatase inserts iron into the ring structure of protoporphyrin IX to produce heme. Deranged production of heme produces a variety of anemias. Iron deficiency, the world's most common cause of anemia, impairs heme synthesis thereby producing anemia. A number of drugs and toxins directly inhibit heme production by interfering with enzymes involved in heme biosynthesis. Lead commonly produces substantial anemia by inhibiting heme synthesis, particularly in children.
Globin Synthesis
Two distinct globin chains (each with its individual heme molecule) combine to form hemoglobin. One of the chains is designated alpha. The second chain is called "non-alpha". With the exception of the very first weeks of embryogenesis, one of the globin chains is always alpha. A number of variables influence the nature of the non-alpha chain in the hemoglobin molecule. The fetus has a distinct non-alpha chain called gamma. After birth, a different non-alpha globin chain, called beta, pairs with the alpha chain. The combination of two alpha chains and two non-alpha chains produces a complete hemoglobin molecule (a total of four chains per molecule).
The combination of two alpha chains and two gamma chains form "fetal" hemoglobin, termed "hemoglobin F". With the exception of the first 10 to 12 weeks after conception, fetal hemoglobin is the primary hemoglobin in the developing fetus. The combination of two alpha chains and two beta chains form "adult" hemoglobin, also called "hemoglobin A". Although hemoglobin A is called "adult", it becomes the predominate hemoglobin within about 18 to 24 weeks of birth.
The pairing of one alpha chain and one non-alpha chain produces a hemoglobin dimer (two chains). The hemoglobin dimer does not efficiently deliver oxygen, however. Two dimers combine to form a hemoglobin tetramer, which is the functional form of hemoglobin. Complex biophysical characteristics of the hemoglobin tetramer permit the exquisite control of oxygen uptake in the lungs and release in the tissues that is necessary to sustain life.
The genes that encode the alpha globin chains are on chromosome 16 (Figure 2). Those that encode the non-alpha globin chains are on chromosome 11. Multiple individual genes are expressed at each site. Pseudogenes are also present at each location. The alpha complex is called the "alpha globin locus", while the non-alpha complex is called the "beta globin locus". The expression of the alpha and non-alpha genes is closely balanced by an unknown mechanism. Balanced gene expression is required for normal red cell function. Disruption of the balance produces a disorder called thalassemia.
Alpha and beta globin gene loci
Figure 2. Schematic representation of the globin gene loci. The lower panel shows the alpha globin locus that resides on chromosome 16. Each of the four alpha globin genes contribute to the synthesis of the alpha globin protein. The upper panel shows the beta globin locus. The two gamma globin genes are active during fetal growth and produce hemoglobin F. The "adult" gene, beta, takes over after birth.