Hemoglobin C (HbC) disease is due to a single amino acid substitution (glutamic acid → lysine) at position 6 in the beta globin chain of the hemoglobin molecule. Hemoglobin S (HbS) is similar to HbC in that it is also formed by an amino acid substitution at position 6 in the beta globin chain. However, patients homozygous for HbC have mild chronic hemolytic anemia, whereas those homozygous for HbS generally have a more severe anemia complicated by vasoocclusive pain episodes. Which of the following properties best accounts for the differing clinical severity between the two conditions?

Question

Hemoglobin C (HbC) disease is due to a single amino acid substitution (glutamic acid → lysine) at position 6 in the beta globin chain of the hemoglobin molecule.  Hemoglobin S (HbS) is similar to HbC in that it is also formed by an amino acid substitution at position 6 in the beta globin chain.  However, patients homozygous for HbC have mild chronic hemolytic anemia, whereas those homozygous for HbS generally have a more severe anemia complicated by vasoocclusive pain episodes.  Which of the following properties best accounts for the differing clinical severity between the two conditions?

Quizplus · Accepted Answer

Globin chains in the hemoglobin tetramer are compactly folded due to nonpolar hydrophobic residues in the interior and charged polar residues on the surface. In sickle cell disease, the usual acidic (negatively charged) glutamic acid (glu) residue at the sixth position on the beta globin chain is replaced by a nonpolar (neutral charge) valine (val) residue, forming hemoglobin S (HbS). This single glu → val substitution leads to the formation of a hydrophobic pocket on the beta globin surface that interacts with a complementary nonpolar residue on another hemoglobin molecule. The hydrophobic interaction causes polymerization of HbS molecules and subsequent erythrocyte sickling, leading to membrane damage and permanent distortion of red blood cells. Red cell sickling is promoted by low oxygen levels, increased acidity, and dehydration. In patients with hemoglobin C (HbC), glu is replaced by a basic polar (positively charged) lysine (lys) residue. Because lys is charged (although it has opposite polarity to glu), there is no hydrophobic interaction between hemoglobin molecules and no polymerization/sickling. However, the positive charge of lys causes HbC to have decreased mobility on electrophoresis. (Choice B) HbS and HbC do not differ significantly from normal hemoglobin in affinity to 2,3-bisphosphoglycerate (2,3-BPG). In addition, weaker interaction with 2,3-BPG would lead to increased oxygen affinity (left shift of the oxygen-hemoglobin dissociation curve), which would help ameliorate sickling. (Choice C) The ability of HbS to polymerize helps stabilize the deoxygenated form, causing a right shift of the oxygen-hemoglobin dissociation curve that facilitates oxygen unloading. In contrast, impaired oxygen unloading occurs with carboxyhemoglobin due to an allosteric change that increases the affinity of the remaining 3 oxygen-binding sites. (Choice D) A glu → val substitution affects the 3-dimensional (tertiary) structure of hemoglobin, but it does not result in a significant change in the alpha helical (secondary) structure. Introducing proline into the primary structure could distort the alpha helix due to proline's rigid cyclic structure. (Choice E) HbS and HbC mutations do not involve amino acids lining the heme pocket. Heme iron oxidation (ferrous [Fe²⁺] → ferric [Fe³⁺]) results in methemoglobin formation. Hemoglobin M disease is a congenital cause of methemoglobinemia due to a mutation in the heme-binding pocket. Educational objective: Hemoglobin S (HbS) contains valine in place of glutamic acid at the sixth amino acid position of the beta globin chain. This promotes hydrophobic interaction among Hb molecules and results in HbS polymerization and erythrocyte sickling.

Hemoglobin C (HbC) Disease Is Due to a Single Amino