Hemoglobin S (HbS) (HbS)

Hemoglobin S (HbS) is an abnormal variant of the oxygen-transport protein hemoglobin, resulting from a point mutation in the HBB gene that replaces glutamic acid with valine at the sixth position of the beta-globin chain (Ingram, 1957). This structural change causes deoxygenated HbS molecules to polymerize into long, rigid insoluble fibers, which is the primary molecular event in sickle cell disease (Eaton & Hofrichter, 1990). These fibers distort red blood cells into a sickle shape, leading to increased blood viscosity, hemolysis, and vaso-occlusive events that cause severe pain and organ damage (NIH, 2023). Therapeutic intervention focuses on preventing this polymerization by either inducing fetal hemoglobin (HbF) to dilute HbS or using direct allosteric modulators (Platt et al., 1984). Voxelotor, a small molecule inhibitor, binds to the alpha-chain of HbS and increases its affinity for oxygen, thereby stabilizing the non-polymerizing oxygenated state (Vichinsky et al., 2019). By reducing the concentration of deoxy-HbS, these treatments aim to prevent the downstream pathological consequences of red cell sickling and improve patient outcomes (FDA, 2019).

Other names

Sickle hemoglobinHemoglobin subunit beta S variantDeoxy-HbSHbS polymerSickle cell hemoglobin

Allosteric stabilization of the oxygenated hemoglobin state to inhibit deoxygenated hemoglobin S polymerization (Vichinsky et al., 2019).