revised April 8, 1998
Hemoglobin synthesis requires the coordinated production of heme and globin.
Heme is the prosthetic group that mediates reversible binding of iron by
hemoglobin. 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 to form delta-aminolevulinate. This molecule is transported
to the cytosol where a series of reactions produce a ring structure called
protoporphyrin IX. This molecule returns to the mitochondrion where iron
is inserted to produce heme. Deranged production of heme produces a variety
of anemias. Iron deficiency, the world's most common cause of anemia, impairs
heme synthesis thereby producing anemia.
"The Heme Molecule"
|Figure 1 Heme molecule.
The protoporphyrin IX ring has an iron moiety in the center which, as a prosthetic group in hemoglobin, forms a coordination complex with oxygen. The heme in hemoglobin reversibly binds oxygen only when the iron is in the ferrous (Fe2+) oxidation state. When the iron is oxidized to the ferric (Fe3+) state, heme does not bind oxygen and the hemoglobin molecule is called "methemoglobin". Free heme without the globin protein of the hemoglobin molecule does not bind oxygen
Two distinct globin chains (each with its individual heme molecule) combine
to form hemoglobin. One of the chains is designated alpha. The second chain
is called "non-alpha". With the exception of the very first weeks
of embryogenesis, one of the globin chains is always alpha. A number of
variables influence the nature of the non-alpha chain in the hemoglobin
molecule. The fetus has a distinct non-alpha chain called gamma. After birth,
a different non-alpha globin chain, called beta, completes the hemoglobin
molecule. The pairing of an alpha chain and a non-alpha chain produces a
hemoglobin dimer. This molecule does not efficiently deliver oxygen, however.
Two dimers combine to form a hemoglobin tetramer, which is the functional
form of hemoglobin. After birth, two alpha chains and two beta chains form
the tetramer of "adult" hemoglobin. Complex biophysical characteristics
of the hemoglobin tetramer permit the exquisite control of oxygen uptake
and release that is necessary to sustain life. The genes that encode the
alpha globin chains are on chromosome 16. Those that encode the non-alpha
globin chains are on chromosome 11. Multiple individual genes are expressed
at each site. Pseudogenes are also present at each location. The alpha complex
is called the "alpha globin locus", while the non-alpha complex
is called the "beta globin locus". The expression of the alpha
and non-alpha genes is closely balanced by an unknown mechanism. Balanced
gene expression is required for normal red cell function. Disruption of
the balance produces a disorder called thalassemia.
Alpha Globin Locus
Each chromosome 16 has two alpha globin genes that, for practical purposes,
are identical. Since each cell has two chromosomes 16, a total of four alpha
globin genes exist in each cell. Each of the four genes produces about one-quarter
of the alpha globin chains needed for hemoglobin synthesis. The mechanism
of this coordination is unknown. Promoter elements exist 5' to each alpha
globin gene. In addition, a powerful enhancer region called the locus control
region (LCR) is required for optimal gene expression. The LCR is many kilobases
upstream of the alpha globin locus. The mechanism by which DNA elements
so distant from the genes control their expression is the source of intense
investigation. The transiently expressed embryonic genes that substitute
for alpha very early in development, designated zeta, are also in the alpha
Beta Globin Locus
The genes in the beta globin locus are arranged sequentially from 3' to 5'
beginning with the gene expressed in embryonic development and ending with
the adult beta globin gene. These are: epsilon, gamma, delta, and beta.
There are two copies of the gamma gene on each chromosome 11. The others
are present in single copies. Therefore, each cell has two beta globin genes,
one on each of the two chromosomes 11 in the cell. These two beta globin
genes express their globin protein in a quantity that precisely matches
that of the four alpha globin genes. The mechanism of this balanced expression
Ontogeny of Hemoglobin Synthesis
The globin genes are activated in sequence during development, moving from
3' to 5' on the chromosome. The zeta gene 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 an elevation 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. Hemoglobin A2, which normally comprises
less than 3% of hemoglobin in adults, is composed of two alpha chains and
two delta chains.
|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)
For more information, see "Hemoglobin: molecular, genetic, and clinical
aspects", Bunn and Forget, Saunders, 1986.