Hemoglobin

Hemoglobin and myoglobin are the oxygentransporting
proteins in vertebrates. Hemoglobin
is found in red blood cells, myoglobin in
muscle. Hemoglobin arose from myoglobin
during the course of evolution. Hemoglobin has
four oxygen-binding sites, myoglobin has one.
Their genes and their three-dimensional protein
structures are completely known in atomic
detail. Different types of hemoglobin that are
optimally adapted to prenatal and postnatal life
have evolved in mammals from an ancestral
gene.

Types of hemoglobin

Hemoglobin consists of four subunits (globin
chains), two pairs of identical polypeptides,
each polypeptide being attached to a heme
group with an oxygen-binding site. The different
kinds of hemoglobins, which are characteristic
of different stages of development
(embryonic, fetal, and postnatal), differ in the
composition of their chains: the hemoglobin of
adults (HbA) contains two ! and two " chains
(!2"2). A small proportion of adult hemoglobin
has two ! and two # chains (HbA2: !2#2).
Hemoglobin formed during the fetal period
(HbF) contains two ! and two $ chains (!2$2). In
the embryonic stage, % chains are joined to & or $
chains (Hb Gower 1: %2&2, and Hb Portland:
%2$2); two ! and two & chains form Hb Gower 2
(!2&2).

Hemoglobins in thalassemia

The thalassemias are a group of genetically determined
disorders of hemoglobin synthesis.
Thalassemia occurs due to the absence or reduced
synthesis of a globin chain, which results
in unstable hemoglobin. It affects either the "
chain ("-thalassemia) or the ! chain (!-thalassemia).
Since the ! chain is a component of both
fetal and adult hemoglobins, the !-thalassemias
(!-thal) are especially severe. Hemoglobins
with four identical globin chains are
completely unstable and incompatible with life
(HbH with four " chains, Hb Bart’s with four $
chains).

Evolution of hemoglobin

Since hemoglobin has four polypeptide chains,
it is a much more efficient oxygen carrier than
the single-chained myoglobin molecule.
Furthermore, the existence of different globin
chains confers a selective advantage in evolution
because their slight functional differences
result in optimal adaptation to the differences
in oxygen concentration before and after birth.
The genes for individual hemoglobin chains
arose from myoglobin by a series of gene duplications
during evolution. The evolutionary age
of the individual Hb chains can be estimated
from their differences in relation to the rate of
mutation. When mammals began to evolve
about 100million years ago, the genes for ! and
" chainswere present, whereas "-like chains (&,
$, #) evolved later.

Globin formation in ontogeny

Different types of globin chains are formed at
different developmental stages: embryonic
hemoglobin during the early embryonic period
(to about the 12thweek), fetal hemoglobin from
about the 12th week until birth, and adult
hemoglobin thereafter. They differ in oxygenbinding
affinity. Thus, oxygen delivery is optimized
for different phases of development.
The site of synthesis also differs. During the
fetal phase, globin chains are synthesized
mainly in the liver, whereas after birth they are
synthesized in red blood cell precursors in the
bone marrow.

Hemoglobin Genes

Each of the globin polypeptide chains is coded
for by a gene. In humans and in other mammals,
the !-like genes (!, ", #) are located together in
a cluster on one chromosome, while the $ genes
are located on another. They are arranged in the
order of their activation during ontogeny.

The !-globin and "-globin genes

The !-globin-like genes (%, "G, "A, #, !) of man
are located on the short arm of chromosome 11
in region 1, band 5.5 (11p15.5). They span about
60000 base pairs (bp), or 60 kb (kilobases), of
DNA.
There are two " genes, "A and "G, which differ
only in codon 136. Codon 136 of "A is alanine,
and of "G, glycine. A pseudogene (&!1) is located
between the A" gene and the # gene. It is
similar to the ! gene, but has been permanently
altered by deletion and an internal stop codon,
so that it cannot code for a functional polypeptide.
A region that jointly regulates these genes
is located upstream (in the 5' direction) from
the ! genes (LCR, long-range control region).
In humans, two $-globin genes are located on
the short arm of chromosome 16 (16p13.11 to
16p13.33) on a DNA segment of about 30 kb. A '
gene, which is active only during the embryonic
period, lies in the 5' direction. Three pseudogenes:
&',&$2, and&$1 are located in between.
A further gene, (, with unknown function, has
been identified in this region.