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OXYGEN (O2) FROM THE LUNGS TO THE CAPILLARIES OF THE TISSUES and returns carbon dioxide to the lungs. HEME is a cyclic tetrapyrrole consisting of four molecules of pyrrole linked by methane bridges. Heterocyclic macromolecules composed of four modified pyrrole subunits interconnected at their α carbon atoms via methyne bridges (=CH-) HEME PERMITS THE REVERSIBLE BINDING OF ONE OXYGEN MOLECULE (OXYGENATION) The iron is held in the center of the heme molecule by bonds to the four nitrogens of the porphyrin ring. THE DIAGRAM, YOU CAN SEE IRON THAT IS HELD IN THE CENTER OF HEME MOLECULES, CAN FORM SIX BONDS; FOUR WITH PORPHYRIN NITROGENS, PLUS TWO ADDITIONAL BONDS, ONE ABOVE AND ONE BELOW THE PLANAR PORPHYRIN RING. NOTE: orphyrins have complex cyclic structures. All porphyrin compounds absorb light intensely at or close to 410 nanometres. Structurally, porphyrin consists of four pyrrole rings THE GLOBIN PROTEIN PARTS ARE SYNTHESIZED BY RIBOSOMES IN THE CYTOSOL. TWO DISTINCT GLOBIN CHAINS (EACH WITH ITS INDIVIDUAL HEME MOLECULE TO FORM HEMOGLOBIN. THE PAIRING OF ONE ALPHA CHAIN AND ONE BETA CHAIN PRODUCES A HGB DIMER (TWO CHAINS). TWO DIMERS COMBINE TO FORM HEMOGLOBIN TETRAMER W/C IS THE FUNCTIONALFORM OF HGB. THE GENES THAT ENCODE THE ALPHA GLOBIN ARE ON CHROMOSOMES 16 WHILE THOSE THAT ENCODE THE BETA GLOBIN ARE ON CHROMOSOME 11 Hemoglobin variants are mutant forms of hemoglobin in a population (usually of humans), caused by variations in genetics. Some well-known hemoglobin variants such as sickle-cell anemia are responsible for diseases, and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants. Some normal hemoglobin types are; Hemoglobin A (Hb A), which is 90% of hemoglobin found in adults, Hemoglobin A2 (Hb A2), which is 2-5% of hemoglobin found in adults, and Hemoglobin F (Hb F), which is not found in adults and is the primary hemoglobin that is produced by the fetus during pregnancy. HEMOGLOBIN A, THE MAJOR HEMOGLOBIN IN ADULTS, IS COMPOSED OF FOUR POLYPEPTIDE CHAINS- TWO ALPHA CHAINS AND TWO BETA CHAINS HELD TOGETHER BY A COVALENT INTERACTIONS.
Erythrocyte homozygous and heterozygous for HbS . The sickling occurs because of a mutation in the hemoglobin geneThe lifetime of an erythrocyte in sickle cell anemia is less than 20 days.000 Americans. and under conditions of low oxygen tension. making them brittle and poorly deformable. it is an autosomal recessive genetic blood disorder caused by a single nucleotide alteration (a point mutation) in the gene for beta globin chain of HbA. and a state of chronic inflammation and hemolysis .HBF composed of 2 alpha and 2 gamma chains HBS composed of 2 alpha and 2 s chains HBa2 composed of 2 aplha and 2 delta chains SICKLE CELL sickle-cell anemia or Hemoglobin S disease is the most common of the red cell sickling disease. compared with 120 days or normal RBC’s . HbS contains 2 normal α-globin chains and 2 mutant β-globin chains in which glutamate at position 6 has been replaced by valine HbS is formed by the substitution of valine for glutamic acid in the second nucleotide of the sixth codon of the β-globin chain of HbA. oxidative damage. The hemoglobin polymers disrupt the attachment of the membrane to the protein cytoskeleton. . HbS is also injurious to the erythrocyte membrane. they are considerably less soluble in deoxygenated blood than normal hemoglobin. This single-point mutation changes the codon determining the amino acid from GAG coding for glutamic acid to GTG coding for valine. rod-shaped polymers. which produces HbS. As such. resulting in exposure of transmembrane protein epitopes and negatively charged glycolipids that are normally found inside the cell. These abnormal hemoglobin polymers aggregate to disrupt the cytoskeleton and distort the shape of the erythrocytes. interaction between the abnormal valine residue and complementary regions on adjacent molecules results in the formation of intracellular. It is the most commmon inherited disorder in USA affecting 80. increased adherence to endothelial cells. Erythrocytes containing mutant HbS have abnormal properties. Thus. blocking blood flow and resulting in local hypoxia In addition to causing the obvious shape change. Subsequent effects of this exposure include cellular dehydration. Although the mutant β-hemoglobin subunits are normal in their ability to bind oxygen. the sickle-shaped cells cannot squeeze through the microcirculatory vessels. unlike normal erythrocytes.
Figure B shows abnormal. genErating a hydrophobic “sticky patch” on the surface of the β subunit of both oxy Hb S and deoxy Hb S Both Hb A and Hb S contain a complementary sticky patch on their surface that is exposed only in the deoxygenated state. it remains soluble in erythrocyte similar to Hb A. FORMING A NETWORK OR . Deoxypolymerizes at low concentrations forming a fibers that distort erythrocytes into the sickle shape. The inset image shows a cross-section of a normal red blood cell with normal hemoglobin. Blocked blood flow can cause pain and organ damage. forming liquid crystals of Hb S polymers that grow in length beyond the diameter of the RBC and causing sickling Figure A shows normal red blood cells flowing freely in a blood vessel. The inset image shows a cross-section of a sickle cell with abnormal (sickle) hemoglobin forming abnormal strands. the nonpolar amino acid valine has replaced the polar surface residue Glu6 of the β subunit. insoluble fibers. Thus a low pO2. Normal red blood cells are disc-shaped and look like doughnuts without holes in the center. On deoxygenation. VALINE REPLACES B6 GLU OF HbA CREATING A STICKY PATCH THAT HAS A COMPLEMENT ON DEOXYHb. When Hb S is fully oxygenated. Hb S in the RBCs become less soluble. DEOXYHEMOGLOBIN S POLYMERIZES INSIDE THE RBC. or crescent. It can also raise the risk for infection SICKLE CELL BY LIPPINCOTT The replacement of the chraged glutamate with the nonpolar valine forms a protrusion on the b globin that fits into a complementary site on the beta chain of another hemoglobin molecule in the cell. deoxy Hb S can polymerize to form long. These cells stiff and sticky. since Hb A lacks the second sticky patch necessary to bind another HB molecule FIGURE: representation of sticky patch on hemoglobin S and its receptor on deoxyA and deoxyS. Binding deoxy H A terminates fiber polymerization. Sickle hemoglobin causes the cells to develop a sickle. sickled red blood cells blocking blood flow in a blood vessel. shape. They move easily through your blood vessels. They tend to block blood flow in the blood vessels of the limbs and organs.HOW SICKLING OCCUR: In Hb S. however. Red blood cells contain an iron-rich protein called hemoglobin .This protein carries oxygen from the lungs to the rest of the body. maintaning a normal biconcave shape of RBCs. At low OXYGEN TENSION. Sickle cells contain abnormal hemoglobin called sickle hemoglobin or hemoglobin S. IN SICKLE CELL HEMOGLOBIN.
If both parents have SCT. THE INTERRUPTION INSIDE THE OXYGEN LEADS TO LOCALIZED ANOXIA (O2 DEPRIVATION) IN THE TISSUE AND CAUSING PAIN AND EVENTUALLY DEATH OF CELLS IN THE VICINITY OF BLOCKAGE. there is a 50% (or 1 in 2) chance that any child of theirs also will have SCT. The main foci of supportive therapy include: . The signs and symptoms of sickle cell disease are caused by the sickling of red blood cells Supportive care has been the mainstay of therapy for SCD. but they can pass SCT on to their children. These individuals have sickle cell trait but usually do not show clinical symptoms and can have a normal life span. If one parent has SCT. Heterozygotes have one normal and one sickle cell gene. Such children will not have symptoms of SCD.FIBROUS POLYMERS THAT STIFEEN AND DISTORT THE CELL PRODUCING RIGID. if the child inherits the sickle cell gene from one of the parents. SUCH SICKLE CELLS FREQUENTLY BLOCKED THE FLOW OF THE BLOOD IN CAPILLARIES. The blood cells of such heterozygotes contain HB S and HB A. MISSHAPEN ERYTHROCYTES. There is the same 25% (or 1 in 4) chance that the child will not have SCD or SCT. there is a 50% (or 1 in 2) chance that any child of this parent will have SCT and an equal 50% chance that the child will not have SCT. How Sickle Cell Trait is Inherited If both parents have SCT. there is a 25% (or 1 in 4) chance that any child of t heirs will have SCD.