Haemoglobin synthesis requires the coordinated production of heme and globin. Heme is the prosthetic group that mediates reversible binding of oxygen by haemoglobin. Globin is the protein that surrounds and protects the heme molecule.
Heme is synthesized in a complex series of steps involving enzymes in the mitochondrion and in the cytosol of the cell. The first step in heme synthesis takes place in the mitochondrion, with the condensation of succinyl CoA and glycine by ALA synthase to form 5-aminolevulic acid (ALA). This molecule is transported to the cytosol where a series of reactions produce a ring structure called coproporphyrinogen III. This molecule returns to the mitochondrion where an addition reaction produces protoporphyrin IX.
The enzyme ferro chelatase inserts iron into the ring structure of protoporphyrin IX to produce heme. Deranged production of heme produces a variety of anaemias.
Two distinct globin chains (each with its individual heme molecule) combine to form haemoglobin. One of the chains is designated alpha. The second chain is called “non-alpha”. The combination of two alpha chains and two non-alpha chains produces a complete haemoglobin molecule (a total of four chains per molecule).
The pairing of one alpha chain and one non-alpha chain produces a haemoglobin dimer (two chains). The haemoglobin dimer does not efficiently deliver oxygen, however. Two dimers combine to form a haemoglobin tetramer, which is the functional form of haemoglobin.
|Embryonic hemoglobins||Fetal hemoglobin||Adult hemoglobins|
|gower 1- zeta(2), epsilon(2)|
gower 2- alpha(2), epsilon (2)
Portland- zeta(2), gamma (2)
|hemoglobin F- alpha(2), gamma(2)||hemoglobin A- alpha(2), beta(2)|
hemoglobin A2- alpha(2), delta(2)
The globin genes are activated in sequence during development, moving from 5′ to 3′ on the chromosome. The zeta gene of the alpha globin gene cluster is expressed only during the first few weeks of embryogensis. Thereafter, the alpha globin genes take over. For the beta globin gene cluster, the epsilon gene is expressed initially during embryogensis. The gamma gene is expressed during fetal development.
The combination of two alpha genes and two gamma genes forms fetal hemoglobin, or hemoglobin F. Around the time of birth, the production of gamma globin declines in concert with a rise in beta globin synthesis. A significant amount of fetal hemoglobin persists for seven or eight months after birth. Most people have only trace amounts, if any, of fetal hemoglobin after infancy. The combination of two alpha genes and two beta genes comprises the normal adult hemoglobin, hemoglobin A.
The delta gene, which is located between the gamma and beta genes on chromosome 11 produces a small amount of delta globin in children and adults. The product of the delta globin gene is called hemoglobin A2, and normally comprises less than 3% of hemoglobin in adults, is composed of two alpha chains and two delta chains.