Sickle Cell Anemia Case Study
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What is hemoglobin?
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-it is the protein molecule in red blood cells -it carries oxygen from the lungs to the bodies tissues - and returns carbon dioxide from the tissues to the body's lungs
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How many sub-units does the hemoglobin A molecule contain?
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2 Alpha Subunits and 2 Beta Subunits
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Where is the heme molecule found?
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The heme is embedded in the center of the porphorin ring, and is essential in the bonding of molecular oxygen to the molecule for transport.
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What are some additional diseases caused due to protein misfolding?
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-Alzheimer's Disease- accumulation of amyloid beta protein in the patients brain - Mad Cow disease- results in Prion Proteins - Multiple Sclerosis- Error in the Chloride Channe;s - Sickle Cell Anemia- Hemoglobin
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How does sickle cell anemia affect the carrier?
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its a hereditary disorder, where the carriers can live normal healthy lives without any symptoms unless the go to a higher altitude or participate in overexertion during exercise
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How does sickle cell anemia affect the homozygous recessive individual?
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-This individual would have a difficult time living a normal and health life, - This individual will have abnormal hemoglobin
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What does low hemoglobin levels denote?
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- That there was a decrease in the need of the heme molecule to carry oxygen because oxygen is depleted at higher altitudes
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What does low hemoglobin levels also cause?
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Because there is the inability or decrease need for the heme molecule to carry oxygen the SERUM IRON LEVELS are also low.
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Why did erythrocytes remain at normal levels?
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bone marrow is producing them continuously to try and compensate for the low level of healthy RBC's present in the blood
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What happens to the erythrocytes as they are being produced?
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The are developed in a premature state and they are lysed and they die
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Why are the hematocrit levels low?
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-They are calculated base on the erythrocyte numbers. - The erythrocytes are lysed before they reach a mature state. - Therefore the portion of total blood by volume is low
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How is hemoglobin electrophoresis used?
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- it is used to separate proteins in the lab - Separates proteins that have more acidic amino acids from those that have more Basic amino acids -
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Which types of proteins move faster?
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Small, Charged or negative proteins move faster
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Which types of proteins move slower?
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Large, positive proteins move slower
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How many bands will the carrier have?
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Carrier will have both bands HBA and HBS
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What types of bands will the normal individual have?
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One HBA band
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What types of bands will the homozygote recessive individual have?
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One HBS band
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Can proteins move beyond their pH values?
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No, therefore it can be detected if the protein is acidic or basic based upon the area within the gel that it aggregates to.
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Why is HBS less anionic (negative) than HBA?
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Because glutamic acid has been replace with valine, which decrease the negative charge associated with the molecule
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What else is different about HBS?
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It moves slower and it is more hydrophobic in comparison to HBA
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What side does HBA move to?
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It moves to the more positive side because it is more negatively charged
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How does HBS structure differ from HBA?
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-Difference between the orientation of the quarternary - it has sticky ends in the beta subunits which attract neighboring subunits - the changes made or more linear rather than globular -shape is distorted - it is less soluble which causes crystal formation
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What happens as a result of the decrease in solubility and the formation of crystals
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- red blood cells lyse and die - depletion of healthy red blood cells - bone marrow producing more immature red blood cells
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What does the oxygen binding curves denote?
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-Increase in oxygen partial pressure promote binding of hemoglobin to O - Decrease in the oxygen partial pressure hemoglobin release oxygen into the muscle, then to lungs for more oxygen
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What does the binding curve exhibit in anemic patients
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- lack of binding to oxygen -CO competes with molecular oxygen - a trace of CO is enough to bind to hemoglobin and displace oxygen CO has 200x's binding to hemoglobin than O
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What was the pressurized chamber used for?
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it was used to show that CO has a greater affinity to hemoglobin than O... - it has 200x's binding to hemoglobin than O
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What is the partial pressure in a Sickle Cell Anemic Person?
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- PP is low - it takes even more pressure for O to bind to hemoglobin - the low affinity is caused due to decrease in size of the porphorin ring -similar but different affinity of O to hemoglobin
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Why did the patient's pain in her arm and leg increase?
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- high altitudes=low partial pressure=less oxygen available - the hemoglobin is deoxygenated and as it becomes more deoxygenated there is a conformational change - which result in the formation of sticky ends
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What are the experimental strategies for treating these patients?
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Asprin derivatives, being studied but not marketed -Hydroxyurea -Blood transfusion
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What prevents a crisis?
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Acetylated HBS and oxygen - Acetylated HBS will not let go of oxygen -which results in less coagulation
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What does hydroxyurea do?
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-Act by increasing the progenitor RBCs expressing HbF -Its less toxic than urea -
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What is significant about HbF?
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Found in infants Has gamma subunits Higher affinity for oxygen
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When are blood transfusions used a a treatment mechanism>
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In very severe cases
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What significant about allosteric proteins
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10. allosteric proteins A. regulated by a small molecule other than substrate B. change seen at the quartenary structure a. can modify the quartenary structure b. example: hemoglobin 1. first molecule will not bind easily but once bound will change conformation and cause it to be fully bound 2. when oxygenated A. no sticky ends B. which means no crystallization
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What is the role of 2,3 Biphosphoglycerate?
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3. 2,3-Bisphosphoglycerate (BPG) A. allosteric modulator of hemoglobin a. modifies affinity of hemoglobin to oxygen b. normal BPG normal S curve c. increase BPG get rightward shift 1. decrease affinity of Hemoglobin 2. typically increased BPG causes hemoglobin to dump O at muscle 3. and in lungs BPG decrease to allow hemoglobin to bind O
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What is the difference between the T and R state?
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T state= not bound to O R= stated bound to O
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• Which of the following amino acid(s) will possess net negative charge at physiological pH?
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◦ aspartic acid ◦ glutamic acid
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• At pH 2.0 the net charge of glutamic acid will be
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◦ +1
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• At pH 9.8 the net charge of glutamic acid will be
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◦ -2
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• In an unknown disease an arginine residue replaces the normal glycine in the affected protein. the arginine differs from glycine in:
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larger molecule affects conformation ◦ basic forms inappropriate salt bridges in the protein ◦ charged at the side chain, may disrupt hydrophobic interactions ALL THE ABOVE
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• In sickle cell enemia, the point mutation in beta chain replaces 6th glutamic acid residue with
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valine ▸ positively charged ▸ more lipophillic
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Which of the following contains gamma subsunits
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◦ Hb F
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• In sickle cell anemic patients, the solubility decreases in
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deoxygenated Hb S ◦ causes crystallization of structure, lysis of RBC and becomes insoluble
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• the pain in her arms and legs while playing and camping is due to
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◦ a lack of adequate O supply to body extremes ◦ increase in deoxygenated Hb S ◦ increase in polymerized Hb S in RBC ◦ increase in deformed RBCs at the small capillaries ◦ all of the above
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the sickle cell heterozygotes are resistent to malaria due to: ◦
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LOW NUMBER OF HEALTHY RED BLOOD CELLS ▸ malaria goes to normal functioning RBCs, and areas with high O ▸ it cannot survive because it's a parasite that needs healthy host cells to continue living ◦ lack of Hb A in RBC's ◦ Presence of Hb S in RBCs ◦ all of the above
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• • This pt's arm and legs hurt more up in the mountain because
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(Wrong) I.low oxygen tension ( Right) .II high 2,3-BPG concentration (Right) III. increased HB S conversion T--> R state
