Hemoglobin is critical for normal oxygen delivery to tissues; it is also present in erythrocytes in such high concentrations that it can alter red cell shape, deformability, and viscosity. Hemoglobinopathies are disorders affecting the structure, function, or production of hemoglobin. These conditions are usually inherited and range in severity from asymptomatic laboratory abnormalities to death in utero. Different forms may present as hemolytic anemia, erythrocytosis, cyanosis, or vasoocclusive stigmata.
Different hemoglobins are produced during embryonic, fetal, and adult life (Fig. 104-1). Each consists of a tetramer of globin polypeptide chains: a pair of α-like chains 141 amino acids long and a pair of β-like chains 146 amino acids long. The major adult hemoglobin, HbA, has the structure α2β2. HbF (α2γ2) predominates during most of gestation, and HbA2 (α2δ2) is minor adult hemoglobin. Embryonic hemoglobins need not be considered here.
The globin genes. The α-like genes (α,ζ) are encoded on chromosome 16; the β-like genes (β,γ,δ,ε) are encoded on chromosome 11. The ζ and ε genes encode embryonic globins.
Each globin chain enfolds a single heme moiety, consisting of a protoporphyrin IX ring complexed with a single iron atom in the ferrous state (Fe2+). Each heme moiety can bind a single oxygen molecule; a molecule of hemoglobin can transport up to four oxygen molecules.
The amino acid sequences of the various globins are highly homologous to one another. Each has a highly helical secondary structure. Their globular tertiary structures cause the exterior surfaces to be rich in polar (hydrophilic) amino acids that enhance solubility, and the interior to be lined with nonpolar groups, forming a hydrophobic pocket into which heme is inserted. The tetrameric quaternary structure of HbA contains two αβ dimers. Numerous tight interactions (i.e., α1β1 contacts) hold the α and β chains together. The complete tetramer is held together by interfaces (i.e., α1β2 contacts) between the α-like chain of one dimer and the non-α chain of the other dimer.
The hemoglobin tetramer is highly soluble but individual globin chains are insoluble. Unpaired globin precipitates, forming inclusions that damage the cell. Normal globin chain synthesis is balanced so that each newly synthesized α or non-α globin chain will have an available partner with which to pair.
Solubility and reversible oxygen binding are the key properties deranged in hemoglobinopathies. Both depend most on the hydrophilic surface amino acids, the hydrophobic amino acids lining the heme pocket, a key histidine in the F helix, and the amino acids forming the α1β1 and α1β2 contact points. Mutations in these strategic regions tend to be the ones that alter oxygen affinity ...