Details on Sickle Cell Anemia as a "molecular disease"
Hemoglobin is a tetrameric protein which is composed of 2 a-globin polypeptide chains and 2 b-globin polypeptide chains. This is a space-filling model of hemoglobin - with each of the 4 polypeptide chains shown in a different color. The small rust-colored ligands are the heme groups (iron atoms chelated with porphyrin rings). As with Tay-Sachs Disease, which is just one of a larger number
of Lysosomal Storage Diseases, Sickle Cell Anemia is just one of
a large number of Hemoglobinopathies
(literally pathologies of hemoglobin).
If hemoglobin contains 2 chains of sickle b-globin (HbS), the hemoglobin molecules tend to stick together because of the additional hydrophobic patches which result from the substitution of Valine for Glutamic Acid. Under anaerobic conditions, sickle cell hemoglobin - HbS - polymerizes into highly elongated cables. In the red blood cell (RBC) such polymers distort its shape and suppleness resulting in a sickle-like appearance in contrast to the normal discoid appearance of normal RBC. The rigid sickle shape impairs the ability of the RBC to pass easily
through small capillary openings. The sickled cells become
entangled with each other and plug up the small
capillaries stopping the delivery of oxygen to the tissues in many
organs.
http://www.emory.edu/PEDS/SICKLE/prod05.htm http://www.emory.edu/PEDS/SICKLE/tutorial/Sickle%20Cell/index.htm Go here for more information on Sickle Cell. PLEIOTROPIC EFFECTS During a sickling incident many tissues and organs are damaged because their blood supply is cut off. Moreover red blood cells cannot regain their normal shape once they have become sickled. They are therefore removed from the blood supply by the spleen. This results in a severe and debilitating under supply of erythrocytes - a condition known as anemia. This in turn taxes the bone marrow which is continually stressed by an excessive demand to produce replacement red blood cells. This leads to many widespread and different types of damage, called pleiotropic effects, all of which however share a single cause - polymerization of HbS.
See an enlarged view of this diagram showing the pleiotropic effects.
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