BCHM 10000 Lecture Notes - Lecture 25: Plasmodium, Fetal Hemoglobin, Blood-Borne Disease
3 Jul 2018
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Sickle cell anemia
– Distorted red blood cells cannot pass as easily through capillaries restricting blood
flow
– Distorted cells frequently lyse, leading to anemia through lowered red blood cell count
and hemoglobin loss
– “Vaso-occlusive crisis” occurs when cells block capillaries in important organs,
particularly the spleen
• Positive feedback of decreased oxygen tension enhances sickling and fuels crisis
– Shortened life expectancy results
• organ failure, acute sickle crisis and stroke are frequent causes of death
– Connection between symptoms and hemoglobin was the first direct association
identified between a molecule and a disease
●Pauling L, Itano HA, Singer SJ, and Wells IC. Sickle Cell Anemia, a Molecular Disease.“
Science 110: 543-548, 1949.
●Not only could diseases be caused by the absence of an enzyme’s activity (PKU,
alcaptonuria), but by a specific amino acid change in a protein itself
• Background
– Hemoglobin is an alpha2/beta2 heterotetramer
– Hemoglobin mutations are specific to one monomer or the other because they are
encoded by separate genes
– Many hemoglobin mutations have been documented
●Hb Hikari is a beta chain mutation (Lys61Asn) with no physiological impact
●HbS is a beta chain mutation (Glu6Val) that causes aggregation
●HbM (Boston) is an alpha chain mutation (His58Tyr) which permits heme iron to
be oxidized so that it cannot bind oxygen
Sickle cell anemia (HbS) is caused by a defect in the beta globin gene – wild type
• Val-His-Leu-Thr-Pro-Glu-Glu-Lys – sickle cell (Hemoglobin S)
Document Summary
Distorted red blood cells cannot pass as easily through capillaries restricting blood flow. Distorted cells frequently lyse, leading to anemia through lowered red blood cell count and hemoglobin loss. Vaso-occlusive crisis occurs when cells block capillaries in important organs, particularly the spleen: positive feedback of decreased oxygen tension enhances sickling and fuels crisis. Shortened life expectancy results: organ failure, acute sickle crisis and stroke are frequent causes of death. Connection between symptoms and hemoglobin was the first direct association identified between a molecule and a disease. Pauling l, itano ha, singer sj, and wells ic. Not only could diseases be caused by the absence of an enzyme"s activity (pku, alcaptonuria), but by a specific amino acid change in a protein itself: background. Hemoglobin mutations are specific to one monomer or the other because they are encoded by separate genes. Hb hikari is a beta chain mutation (lys61asn) with no physiological impact.
