Hemoglobin subunit beta (HBB) (HBB)

Hemoglobin III is a historical and context-dependent designation primarily identifying Hemoglobin C (HbC), a structural variant of the human Hemoglobin subunit beta (HBB) resulting from a specific glutamic acid to lysine substitution at position 6 (E6K). Discovered in 1950, it was initially named Hemoglobin III as the third electrophoretically distinct human hemoglobin identified after Hemoglobin A and Hemoglobin S. While individuals with the Hemoglobin C trait are often asymptomatic, homozygous Hemoglobin C disease and compound heterozygous Sickle-Hemoglobin C (HbSC) disease are clinically significant hemoglobinopathies characterized by microcytosis, splenomegaly, and mild to moderate hemolytic anemia. The HBB subunit is a major therapeutic target for allosteric modulators like voxelotor, which stabilize the oxygenated state of hemoglobin to prevent the pathological consequences of variant polymerization. Beyond the historical nomenclature for HbC, the term "Hemoglobin III" is also used in bioinorganic chemistry to refer to Methemoglobin (Fe-III), the oxidized ferric state of hemoglobin that is incapable of oxygen transport and is the primary target for reductive therapies such as methylene blue. Additionally, "Hemoglobin III" refers to specific monomeric or dimeric oxygen-reactive hemoglobins in invertebrates, such as those found in the clam Lucina pectinata and the midge Chironomus thummi. These proteins are extensively used in structural biology and biophysics as models for understanding ligand binding and as templates for developing stable hemoglobin-based oxygen carriers (HBOCs) for use as blood substitutes.

Other names

Hemoglobin CHbCHemoglobin IIIBeta-globinMethemoglobinFerric hemoglobinHemoglobin subunit beta variant C

Direct allosteric modulation of hemoglobin tetramers to increase oxygen affinity and prevent polymerization; chemical or enzymatic reduction of the ferric heme iron in methemoglobin; induction of fetal hemoglobin expression to mitigate defective beta-globin production.