SICKLE-CELL-ANEMIA_37541

SICKLE-CELL-ANEMIA_37541 - SICKLE CELL ANEMIA Historical...

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SICKLE CELL ANEMIA Historical Summary 1904 Abnormal “pear shaped elongate forms” of red cells first observed by a medical intern on a blood smear from a West Indian dental student. Findings published in 1910. 1922 Similar observations; falciform (sickle) shape of red cells noted, leading to name of disease. 1927 Sickling associated with deoxygenation of red cells. Cells that were irreversibly sickled even in presence of oxygen were later proposed to have a membrane defect. 1949 Electrophoresis of hemoglobin (HbS) from sickle cell anemia patient demonstrated it migrated differently from normal hemoglobin (HbA). Latent form (sickle cell trait) showed both HbS and HbA. First instance that a genetic disorder traced directly to an abnormal protein
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SICKLE CELL ANEMIA Historical Summary (cont’d) 1950 Ingram showed that HbA and HbS differ by a single amino acid. He did this by degrading Hb with trypsin and separated resulting peptides by 2 dimensional paper chromatography (“fingerprinting”). Comparing peptide patterns from HbA and HbS, a single peptide differed in position.The change subsequently shown to be a replacement of an acidic (Glu) with a hydrophobic amino acid (Val) at position 6 of the beta chain. 1975 X-ray crystallographic structure of HbS solved. Provided evidence that when deoxygenated, HbS is much less soluble than corresponding HbA. Abnormal tetramers polymerize to form linear filaments which then associate into larger fibers.Their accumulation deforms red cells, damages their membranes and renders them stiff and inflexible.
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REVIEW OF HEMOGLOBIN PROPERTIES
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CHARACTERISTICS OF GLOBIN PROTEINS · Single polypeptide chain of ~150 amino acids · High proportion of α -helix: 75% of the amino acids are associated with 8 α -helices · α -helices are organized into a tightly packed, nearly spherical, globular tertiary structure · Highly soluble: polar amino acids on the exterior surface of the protein · Each globin contains one noncovalently bound heme group
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Hemoglobin · Synthesized in RBC precursor cells: reticulocytes and erythroblasts · Synthesis is tightly controlled and dictated by the concentration of heme Tetramer of 2 α -globin and 2 β - globin chains Best described as a dimer of the heterodimer ( αβ )
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INTERACTIONS WITH O 2 * Can bind up to 4 O 2 molecules * Binding of O 2 is cooperative: the binding of 1 O 2 influences the binding of another.
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DEOXYGENATED VS. OXYGENATED HEMOGLOBIN As deoxygenated hemoglobin becomes oxygenated, significant structural changes take place the proximal histidine and its helix shift one heterodimer rotates and slides relative to the other existing noncovalent bonds are broken and replaced by new ones Approximately 30 amino acids participate in the noncovalent (hydrogen and/or electrostatic) interactions between the 2 heterodimers · Interactions between the two heterodimers are stronger in the T (tense)- state = deoxygenated hemoglobin · These interactions are weaker in the R (relaxed)-state = oxygenated hemoglobin · The R-state has a higher affinity for O 2 than the T-state
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DEOXYGENATED VS. OXYGENATED
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This note was uploaded on 01/23/2011 for the course BCHS 4361 taught by Professor Echberg during the Spring '09 term at University of Houston.

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SICKLE-CELL-ANEMIA_37541 - SICKLE CELL ANEMIA Historical...

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