Question

Case 8 Hemoglobin, the Oxygen Carrier Focus concept A mutation in the gene for hemoglobin results in an altered protein responsible for the disease sickle cell anemia. An understanding of the biochemistry of the disease may suggest possible treatments Prerequisite Hemoglobin structure and function concepts Background Normal adult hemoglobin is called Hemoglobin A (Hb A). Ninety-eight percent ofaduk hemoglobin is Hb A and 2% is Hb A. There are other forms of hemoglobin. For example, the deve loping fetus has a diferent kind ofhemoglobin than most normal adults. Fetal hemoglobin (or Hemoglobin F) consists of two a chains and two y chains, whereas adult hemoglobin (Hemoglobin A) consists oftwo a chains and two B chains. Fetal hemoglo bin is symhesized beginning at the third month of gestation and continues up through birth. After the neonate is bom, he moglobin F synthesis dec lines (because synthesis of the y chain declines) and hemoglobin A is synthes ized (because synthesis of Bchains begins). By the time the baby is six months old, 98 % of its hemog lobin is Hemoglobin A. There is also a mutant fom of hemoglobin called Hemoglobin S which is found in persons with the disease sickle cell anemia. The disease sickle cell anemia is one of the major health problems facing the African-American community. The Workd Health Organization estimates that 250,000 babies world wide are born with sickle cell anemia. Currently there is no cure. A person afflicted with sickle cell anemia has inherited a defective gene from each parent. (Parents who are carriers of the sickle cell gene are heterozygous AS, whereas the person aflicted with sickle cell anemia is SS; mon-carriers are designated AA.) The defective gene is the one coding for the B-chain. The amino acid at position 6 on each B chain has been mutated from a glutamate to a valine. Normal a chains have a decreased affinity for the mutated B chains; thus assembly of the HbS tetramer is more difficult. Red blood cells containing HbS form a sickle shape because the Hb S molecules polymerize. Hb S molecules are more likely to polymerize when in the deoxygenated T fom than in the oxygenated R form The polymerized Hb deforms the normal discoid shape ofthe red blood cels, producing a sick le-shaped cell. The sickle shaped red blood cells become trapped in capillaries and organs, depriving the victim of adequate oxygen supply and causing chronic pain and organ damage In this case we will consider our patient, a 10-year-old black male child named Michacl B, who was admitted to the hospital because he was experienc ing severe chest pain. He had been hospitalized on several previous occasions for vaso-occlusive episodes that caused him to experience severe pain that could not be manag ed with non-prescription drugs such as ibuprofen He was slightly jaundiced, short of breath and casily tired, and feverish A chest x-ray was taken and was abnormal. An arterial blood sample showed a po: value of 6 kPa (normal is 10-13 kPa) 2. Why do you think that Hb S molecules would be likely to clump together whereas Hb A molecules do not? 3. In the emergency room, oxygen (100 %) was administered to the patient. (Inspired air nomally is about 20% oxygen.) Why was this an effective treatment? 4. You recall reading in the medical lit erature about a dramatic new drug treatment for sickle cell anemia, and you'd like to try it on this pat ient. The drug is hydroxyurea, and is thought to function by stimulating the afflicted person's synthesis of fetal hemoglo bin. Exactly how hydroxyurea stimu lated fetal hemoglobin synthesis is unclear, but it is believed that hydroxyurea is metabolized to NO, which binds to a soluble guanylate eyelase enzyme which then catalyzes the synthesis of a second messenger, cyelic GMP (cGMP). The cGMP interacts with transcription factors in a manner that is not completely understood to induce the transcription (and then translation) of the fetal hemoglobin gene. a. In a clinical study, patients who took hydroxyurea showed a 50 % reduction in frequency of ho spital admissions for severe pain, and there was also a decrease in the frequency of fever and abnormal chest x-rays. Why would increasing the synthesis of fetal hemoglobin result in alleviating the symptoms of sick le cell anemia? b. Medical practioners who used hydroxyurea as a treatment for sickle cell anemia noted that their patients seemed to bene fit from the administration of the drug long before the synthesis of fetal hemoglobin had time to take effect. It has recently been detemined that hydroxyurea can react directly with the iron ion of oxy- and deoxyHb to fom iron nitrosyl hemoglobin (HbNO). Why would this be of benefit to the sickle-cell anemic patient? c. And finally, hydroxyurea has been sho wn to produce NO directly, in less than an hour after hydroxyurea administration. It's also possible that HbNO could produce NO, either directly or indirectly. NO is an important second messenger which, even in nanomolar amounts, stimulat es vaso dilation How coukd NO production help the sickle-cell anemic patient?

Answer 1

2) Haemoglobin is a tetrameric protein, consists of two alpha and two beta chains which are responsible for oxygen transportation in blood. Sickle cell diseases are caused due to the substitution of polar amino acid with at non-polar valine at the 6th position of each beta chain. Due to the mutation, the beta chain becomes sticky in low oxygen conditions as valine sticks out of the chain and interacts with neighbouring non-polar amino acids. HbS molecules in haemoglobin polymerize in deoxygenated T form than in oxygenated R form. This polymerization of HbS causes the distortion of red blood cells into a sickle. When HbS losses oxygen, then hydrophobic patch gets exposed to both normal Hb and HbS where valine interacts and results in the formation of fibrous polymer which causes distortion of red blood cell into a sickle shape. As HbS has less tendency to bind with oxygen, hence fibrous polymer formed is less flexible and has an increased tendency of forming lumps.