HAEMOGLOBIN

When we breathe in oxygen, the red blood cells transport it around to every cell in
the body – a critical process that has far-reaching evolutionary consequences. The advent
of aerobic respiration, which added the oxygen-utilising tricarboxylic acid cycle and
electron transport system onto anaerobic glycolysis, allowed aerobic organisms to extract
18 times more energy from glucose in the form of ATP. Initially, organisms relied on
diffusion to transport oxygen to their cells, an inefficient system that kept them
microscopic in size. Then with the development of the body cavity came a primitive
circulatory system involving the flow of interstitial fluid through the action of muscular
movement; yet, body size remained small, as this system of circulation was limited in its
effectiveness. Nematode worms have a primitive type of body cavity (pseudocoelom)
and circulation; these tiny animals consist of just under a 1000 cells and as such are
barely visible with the naked eye. With the advent of a true circulatory system to
transport highly specialised red blood cells close to every cell in the body no matter how
large the organism, so that oxygen could now reach all cells, body size was able to
expand radically up to the largest animal to currently inhabit the earth: the blue whale,
which can weight up to 150 tons and stretch 100 feet in length from head to tail.

Haemoglobin, an Oxygen Carrier

A drop of blood contains millions of red blood

cells, or erythrocytes. These specialised cells are like
flattened discs, which gives them a much greater surface
area with which to exchange oxygen and carbon dioxide in
the lungs and with body cells. Red blood cells are able to
carry oxygen so efficiently because of a special protein
Red blood cells inside them: haemoglobin. In fact, it is the haemoglobin
that is responsible for the colour of the red blood cell. Haemoglobin contains a haem
prosthetic group that has an iron atom at its centre. When the iron is bound to oxygen,
the haem group is red in colour (oxyhameoglobin), and when it lacks oxygen
(deoxygenated form) it is blue-red. As blood passes through the lungs, the haemoglobin
picks up oxygen because of the increased oxygen pressure in the capillaries of the lungs,
and can then release this oxygen to body cells where the oxygen pressure in the tissues is
lower. In addition, the red blood cells can pick up the waste product, carbon dioxide,
some of which is carried by the haemoglobin (at a different site from where it carries the
oxygen), while the rest is dissolved in the plasma. The high carbon dioxide levels in the
tissues lowers the pH, and the binding of haemoglobin to carbon dioxide causes a
conformational change that facilitates the release of oxygen. The carbon dioxide is then
released once the red blood cells reach the lungs.

Haemoglobin is composed of four polypeptide chains, which in adults consist of

two alpha ( ) globin chains and two beta ( ) globin chains (i.e. 2 2). Each
polypeptide has a haem prosthetic group attached, where each haem can bind one oxygen

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molecule - so there are four haem groups per haemoglobin molecule that together bind
four oxygen molecules.

3-dimensional structure of hemoglobin. The four subunits are shown in red

and yellow, and the heme groups in green.

Hemoglobin or haemoglobin (frequently abbreviated as Hb) is the iron-containing

oxygen-transport metalloprotein in the red cells of the blood in mammals and other
animals. Hemoglobin in vertebrates transports oxygen from the lungs to the rest of the
body, such as to the muscles, where it releases the oxygen load. Hemoglobin also has a
variety of other gas-transport and effect-modulation duties, which vary from species to
species, and which in invertebrates may be quite diverse.

The name hemoglobin is the concatenation of heme and globin, reflecting the fact that
each subunit of hemoglobin is a globular protein with an embedded heme (or haem)
group; each heme group contains an iron atom, and this is responsible for the binding of
oxygen. The most common types of hemoglobin contains four such subunits, each with
one heme group.

Mutations in the genes for the hemoglobin protein in humans result in a group of
hereditary diseases termed the hemoglobinopathies, the most common members of which
are sickle-cell disease and thalassemia. Historically in human medicine,
hemaglobinopathies were the first diseases to be understood in mechanism of
dysfunction, down to the molecular level.

Hemoglobin is synthesized in the mitochondria of the immature red blood cell throughout
its early development from the proerythroblast to the reticulocyte in the bone marrow,
when the nucleus has been lost. Even after the loss of the nucleus, residual ribosomal

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RNA allow further synthesis of Hb until the reticulocyte loses its RNA on entering the
vasculature. Hemoglobin is chemically represented by (C2952H4664N812O832S8Fe4).

Structure

Heme group

The hemoglobin molecule in humans is an assembly of four globular protein subunits.

Each subunit is composed of a protein chain tightly associated with a non-protein heme
group.

Each individual protein chain arranges in a set of alpha-helix structural segments

connected together in a globin fold arrangement, so called because this arrangement is the
same folding motif used in other heme/globin proteins such as myoglobin. This folding
pattern contains a pocket which is suitable to strongly bind the heme group.

A heme group consists of an iron atom held in a heterocyclic ring, known as a porphyrin.
This iron atom is the site of oxygen binding. The iron atom is bonded equally to all four
nitrogens in the center of the ring, which lie in one plane. Two additional bonds
perpendicular to the plane on each side can be formed with the iron to a fifth and sixth
bonding position, one connected strongly to the protein, the other available for binding of
an oxygen molecule. The iron atom may either be in the Fe2+ or Fe3+ state, but
ferrihemoglobin (methemoglobin) (Fe3+) cannot bind oxygen.

The Fe2+ in hemoglobin may exist in either a high-spin (deoxygenated) or low-spin

(oxygenated) state, according to population of the iron (II) d-orbital structure with its 6
available d electrons, as understood in crystal field theory. With the binding of an oxygen
molecule as a sixth ligand to iron, the iron (II) atom finds itself in a octahedral field
(defined by the six ligand points of the four porphyrin ring nitrogens, the histamine

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nitrogen, and the O2). In these circumstances, with strong-field ligands, the five d-orbitals
(these are the “3d” orbitals of the iron) undergo a splitting in energy between two of the
d-orbitals which point directly in the direction of the ligands (dz2 and dx2-y2 orbitals,
hybridized in these circumstances into two eg orbitals), and three of the d-orbitals which
are pointed in off-directions (the dxy ,dxz, and dyz, hybridized in these circumstances into
three t2g orbitals).

When oxygen is bound to Fe2+ in heme, all 6 d-electrons of the iron atom are forced into
the three lower-energy t2g orbitals, where they must all be paired (see crystal field theory
for diagram). This produces the “low-spin” state of oxyhemoglobin. The sharp high-
energy of transition between the t2g and empty eg states of d-orbital electrons in
oxyhemoglobin is responsible for the bright red color of the substance. When oxygen
leaves, the Fe2+ is allowed to move out of the porphyrin ring plane, away from its five
ligands toward the empty space formerly occupied by the O2, and in these circumstances
eg orbital energies drop and t2g electrons move into them. This causes the iron atom to
expand and increase its net spin, as d-orbitals become populated with unpaired electrons.
In these circumstances, the absorption spectrum becomes broader, with smaller transition
levels, producing the dark color of deoxyhemoglobin.

In adult humans, the most common hemoglobin type is a tetramer (which contains 4
subunit proteins) called hemoglobin A, consisting of two α and two β subunits non-
covalently bound, each made of 141 and 146 amino acid residues, respectively. This is
denoted as α2β2. The subunits are structurally similar and about the same size. Each
subunit has a molecular weight of about 16,000 daltons, for a total molecular weight of
the tetramer of about 64,000 daltons. Hemoglobin A is the most intensively studied of the
hemoglobin molecules.
[[Image:|px|Hemoglobin chemical
The four polypeptide chains are bound to structure]]
each other by salt bridges, hydrogen bonds
and hydrophobic interaction. There are two hemoglobin, beta
kinds of contacts between the α and β chains: Identifiers
α1β1 and α1β2. Symbol(s) HBB
Entrez 3043
Types of hemoglobins in humans OMIM 141900
RefSeq NM_000518
In the embryo: UniProt P68871
PDB [6]
• Gower 1 (ξ2ε2) Other data
• Gower 2 (α2ε2) (PDB 1A9W) EC number [7]
• Hemoglobin Portland (ξ2γ2) Locus Chr. 11 p15.5

In the fetus:

• Hemoglobin F (α2γ2) (PDB 1FDH)

In adults:

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 • Hemoglobin A (α2β2) (PDB 1BZ0) - The most common type.
• Hemaglobin A2 (α2δ2) - δ chain synthesis begins late in the third trimester and in
adults, it has a normal level of 2.5%
• Hemoglobin F (α2γ2) - In adults Hemoglobin F is restricted to a limited population
of red cells called F cells.

Binding of ligands

Binding and release of ligands induces a conformational (structural) change in

hemoglobin. Here, the binding and release of oxygen illustrates the structural differences
between oxy- and deoxyhemoglobin, respectively.

As discussed above, when oxygen is bound to Fe2+ in heme, all 6 d-electrons are forced
into three lower-energy t2g orbitals, where they are all paired. This causes contraction of
the iron atom, and causes it to move back into the center of the porphyrin ring plane (see
moving diagram). At the same time, the porphyrin ring plane itself is pushed away from
the oxygen and toward the histamine interacting at the other pole of the iron. The
interaction here forces the ring plane sideways toward the outside of the tetramer, and
also induces a strain on the protein helix containing the histamine, as it moves nearer the
iron. This causes a tug on this peptide strand which tends to open up heme units in the
remainder of the molecule, so that there is more room for oxygen to bind at their heme
sites.

In the tetrameric form of normal adult hemoglobin, the binding of oxygen is thus a
cooperative process. The binding affinity of hemoglobin for oxygen is increased by the
oxygen saturation of the molecule, with the first oxygens bound influencing the shape of
the binding sites for the next oxygens, in a way favorable for binding. This positive
cooperative binding is achieved through steric conformational changes of the hemoglobin
protein complex as discussed above, i.e. when one subunit protein in hemoglobin
becomes oxygenated, this induces a conformational or structural change in the whole
complex, causing the other subunits to gain an increased affinity for oxygen. As a

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consequence, the oxygen binding curve of hemoglobin is sigmoidal, or S-shaped, as
opposed to the normal hyperbolic curve associated with noncooperative binding.

Hemoglobin's oxygen-binding capacity is decreased in the presence of carbon monoxide

because both gases compete for the same binding sites on hemoglobin, carbon monoxide
binding preferentially in place of oxygen. Carbon dioxide occupies a different binding
site on the hemoglobin. Through the enzyme carbonic anhydrase, carbon dioxide reacts
with water to give carbonic acid, which decomposes into bicarbonate and protons:

CO2 + H2O → H2CO3 → HCO3- + H+

The sigmoidal shape of hemoglobin's oxygen-dissociation curve results from cooperative

binding of oxygen to hemoglobin.

Hence blood with high carbon dioxide levels is also lower in pH (more acidic).
Hemoglobin can bind protons and carbon dioxide which causes a conformational change
in the protein and facilitates the release of oxygen. Protons bind at various places along
the protein, and carbon dioxide binds at the alpha-amino group forming carbamate.
Conversely, when the carbon dioxide levels in the blood decrease (i.e., in the lung
capillaries), carbon dioxide and protons are released from hemoglobin, increasing the
oxygen affinity of the protein. This control of hemoglobin's affinity for oxygen by the
binding and release of carbon dioxide and acid, is known as the Bohr effect.

The binding of oxygen is affected by molecules such as carbon monoxide (CO) (for
example from tobacco smoking, cars and furnaces). CO competes with oxygen at the
heme binding site. Hemoglobin binding affinity for CO is 200 times greater than its
affinity for oxygen, meaning that small amounts of CO dramatically reduces
hemoglobin's ability to transport oxygen. When hemoglobin combines with CO, it forms
a very bright red compound called carboxyhemoglobin. When inspired air contains CO
levels as low as 0.02%, headache and nausea occur; if the CO concentration is increased
to 0.1%, unconsciousness will follow. In heavy smokers, up to 20% of the oxygen-active
sites can be blocked by CO.

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In similar fashion, hemoglobin also has competitive binding affinity for cyanide (CN-),
sulfur monoxide (SO), nitrogen dioxide (NO2), and sulfide (S2-), including hydrogen
sulfide (H2S). All of these bind to iron in heme without changing its oxidation state, but
they nevertheless inhibit oxygen-binding, causing grave toxicity.

The iron atom in the heme group must be in the Fe2+ oxidation state to support oxygen
and other gases' binding and transport. Oxidation to Fe3+ state converts hemoglobin into
hemiglobin or methemoglobin (pronounced "MET-hemoglobin"), which cannot bind
oxygen. Hemoglobin in normal red blood cells is protected by a reduction system to keep
this from happening. Nitrogen dioxide and nitrous oxide are capable of converting a
small fraction of hemoglobin to methemoglobin, however this is not usually of medical
importance (nitrogen dioxide is poisonous by other mechanisms, and nitrous oxide is
routinely used in surgical anesthesia in most people without undue methemoglobin
buildup).

In people acclimated to high altitudes, the concentration of 2,3-bisphosphoglycerate (2,3-

BPG) in the blood is increased, which allows these individuals to deliver a larger amount
of oxygen to tissues under conditions of lower oxygen tension. This phenomenon, where
molecule Y affects the binding of molecule X to a transport molecule Z, is called a
heterotropic allosteric effect.

A variant hemoglobin, called fetal hemoglobin (HbF, α2γ2), is found in the developing
fetus, and binds oxygen with greater affinity than adult hemoglobin. This means that the
oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher percentage of
hemoglobin has oxygen bound to it at lower oxygen tension), in comparison to that of
adult hemoglobin. As a result, fetal blood in the placenta is able to take oxygen from
maternal blood.

Degradation of hemoglobin in vertebrate animals

When red cells reach the end of their life due to aging or defects, they are broken down,
and the hemoglobin molecule broken up and the iron recycled. When the porphyrin ring
is broken up, the fragments are normally secreted in the bile by the liver. The major final
product of heme degradation is bilirubin. Increased levels of this chemical are detected in
the blood if red cells are being destroyed more rapidly than usual. Improperly degraded
hemoglobin protein or hemoglobin that has been released from the blood cells too rapidly
can clog small blood vessels, especially the delicate blood filtering vessels of the kidneys,
causing kidney damage.

Diagnostic use

Hemoglobin levels are amongst the most commonly performed blood tests, usually as
part of a full blood count or complete blood count. Results are reported in g/L, g/dL or
mol/L. For conversion, 1 g/dL is 0.621 mmol/L. If the total hemoglobin concentration in
the blood falls below a set point, this is called anemia. Anemias are further subclassified
by the size of the red blood cells, which are the cells which contain hemoglobin in

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vertebrates. They can be classified as microcytic (small sized red blood cells), normocytic
(normal sized red blood cells), or macrocytic (large sized red blood cells).

Glucose levels in blood can vary widely each hour, so one or only a few samples from a
patient analyzed for glucose may not be representative of glucose control in the long run.
For this reason a blood sample may be analyzed for Hb A1c level, which is more
representative of glucose control averaged over a longer time period (determined by the
half-life of the individual's red blood cells, which is typically 50-55 days). People whose
Hb A1c runs 6.0% or less show good longer-term glucose control. Hb A1c values which are
more than 7.0% are elevated. This test is especially useful for diabetics.

This Hb A1c level is only useful in individuals who have red blood cells (RBCs) with
normal survivals (i.e., normal half-life). In individuals with abnormal RBCs, whether due
to abnormal hemoglobin molecules (such as Hemoglobin S in Sickle Cell Anemia) or
RBC membrane defects - or other problems, the RBC half-life is frequently shortened. In
these individuals an alternative test called "fructosamine level" can be used. It measures
the degree of glycation (glucose binding) to albumin, the most common blood protein,
and reflects average blood glucose levels over the previous 18-21 days, which is the half-
life of albumin molecules in the circulation.

Hemoglobin in the biological range of life

Hemoglobin is by no means unique to vertebrates; there are a variety of oxygen transport

and binding proteins throughout the animal (and plant) kingdom. Other organisms
including bacteria, protozoans and fungi all have hemoglobin-like proteins whose known
and predicted roles include the reversible binding of gaseous ligands. Since many of these
proteins contain globins, and also the heme moiety (iron in a flat porphyrin support),
these substances are often simply referred to as hemoglobins, even if their overall tertiary
structure is very different from that of vertebrate hemoglobin. In particular, the distinction
of “myoglobin” and hemoglobin in lower animals is often impossible, because some of
these organisms do not contain muscles. Or they may have a recognizable separate
circulatory system, but not one which deals with oxygen transport (for example, many
insects and other arthropods). In all these groups, heme/globin containing molecules
(even monomeric globin ones) which deal with gas-binding are referred to as
hemoglobins. In addition to dealing with transport and sensing of oxygen, these
molecules may also deal with NO, CO2, sulfide compounds, and even O2 scavenging in
environments which must be anaerobic. They may even deal with detoxification of
chlorinated materials in a manner analogous to heme-containing P450 enzymes and
peroxidases.

The structure of hemoglobins varies across species. Hemoglobin occurs in all kingdoms
of organism, but not in all organisms. Single-globin hemoglobins tend to be found in
primative species such as bacteria, protozoa, algae, and plants. Nematode worms,
moluscs and crustaceans, however, many contain very large multisubunit molecules much
larger than those in vertebrates. Particularly worth noting are chimeric hemoglobins
found in fungi and giant annelids, which may contain both globin and other types of

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proteins [PMID 11274340]. One of the most striking occurrences and uses of hemoglobin
in organisms occurs in the (up to) 2.4 meter giant tube worm (Riftia pachyptila also
called Vestimentifera) which populates ocean volcanic vents at the sea floor. These
worms have no digestive tract, but instead contain a population of bacteria constituting
half the organism’s weight, which react H2S from the vent and O2 from the water to
produce energy to make food from H2O and CO2. These organisms end with a deep red
fan-like structure ("plume") which extends into the water and which absorbs H 2S and O2
for the bacteria, and also absorbs CO2 for use as synthetic raw material (after the manner
of photosynthetic plants). The bright red color of the structures results from several
extraordinarily complex hemoglobins found in them which contain up to 144 globin
chains (presumably each including associated heme structures). These tube worm
hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and
indeed to also carry sulfide, without being completely "poisoned" or inhibited by this
molecule, as hemoglobins in most other species are [PMID 8621529].

Other biological oxygen-binding proteins

Myoglobin: Found in the muscle tissue of many vertebrates including humans (gives
muscle tissue a distinct red or dark gray color). Is very similar to hemoglobin in structure
and sequence, but is not arranged in tetramers, it is a monomer and lacks cooperative
binding and is used to store oxygen rather than transport it.

Hemocyanin: Second most common oxygen transporting protein found in nature. Found
in the blood of many arthropods and molluscs. Uses copper prosthetic group instead of
iron heme groups and is blue in color when oxygenated.

Hemerythrin: Some marine invertebrates and a few species of annelid use this iron
containing non-heme protein to carry oxygen in their blood. Appears pink/violet when
oxygenated, clear when not.

Chlorocruorin: Found in many annelids, and is very similar to Erythrocruorin, but the
heme group is significantly different in structure. Appears green when deoxygenated and
red when oxygenated.

Vanabins: Also known as Vanadium Chromagen are found in the blood of Sea squirt
and are hypothesised to use the rare metal Vanadium as its oxygen binding prosthetic
group, but this hypothesis is unconfirmed.

Erythrocruorin: Found in many annelids, including earthworms. Giant free-floating

blood protein, contains many dozens even hundreds of Iron heme containing protein
subunits bound together into a single protein complex with a molecular masses greater
than 3.5 million daltons.

Pinnaglobin: Only seen in the mollusk Pinna squamosa. Brown manganese-based

porphyrin protein.

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Leghemoglobin: In leguminous plants, such as alfalfa or soybeans, the nitrogen fixing
bacteria in the roots are protected from oxygen by this iron heme containing, oxygen
binding protein.

Foetal Haemoglobin, in a Class of its Own

The foetus has different haemoglobin needs from that of an adult. The foetus
receives its blood supply via the umbilical vein from the placenta. However, by the time
the blood has reached the placenta, much of its oxygen has already been used up by the
mother. Consequently, foetal haemoglobin needs to be able to bind oxygen with a higher
affinity than maternal blood, if enough oxygen is to reach the foetus. Initially, embryonic
haemoglobin is the main form, consisting of at least three types: Gower1 (zeta2 epsilon2,
or 2 2), Gower2 (alpha2 epsilon2, or 2 2), and Portland (zeta2 gamma2, or
2 2). The and globin chains are unique to embryonic haemoglobin and
appear to be synthesised almost entirely in the yolk sac.

After the second month of development, the foetus switches to foetal

haemoglobin (haemoglobin F; alpha2 gamma2, or 2 2). At birth, approximately 50-
95% of the child’s haemoglobin is foetal haemoglobin, but after six months, these levels
decline and adult haemoglobin (haemoglobin A, 2 2) becomes the predominant
form, as it is better suited to the oxygen transport requirements after birth. There is also
haemoglobin A2 (alpha2 delta2, or 2 2), which is synthesised late in the third
trimester and continues into adulthood at a level of 2.5%.

Haemoglobin and High Altitudes

People living at high altitudes, such as in the Tibetan Plateau or the Andes
Mountains, have developed unique and often different ways to cope with the reduced
amount of oxygen available at higher altitudes. Natives of the Andes Mountains in South
America have a higher concentration of haemoglobin in their blood, allowing more
oxygen to be carried by the same volume of blood. However, there are other means of
coping with high altitudes. For instance, the people living in the Tibetan Plateau have
doubled their nitric oxide levels. Nitric oxide is a blood vessel dilator, which is thought
to boost the uptake of oxygen.

Haemoglobin and Disease

Decreased levels of hemoglobin, with or without an absolute decrease of red blood cells,
leads to symptoms of anemia. Anemia has many different causes, although iron
deficiency and its resultant iron deficiency anemia are the most common causes in the
Western world. As absence of iron decreases heme synthesis, red blood cells in iron
deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic
(smaller than normal). Other anemias are rarer. In hemolysis (accelerated breakdown of
red blood cells), associated jaundice is caused by the hemoglobin metabolite bilirubin,
and the circulating hemoglobin can cause renal failure.

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Anaemia may be caused by excessive loss of blood, by destruction of red cells or by
decreased red cell production. Only the first two of these causes will be discussed here
(see separate factsheet for anaemia caused by decreased red blood cell production).
Excessive loss of blood may be sudden:

• Accidents
• Childbirth
• Surgery
• A ruptured blood vessel

Excessive blood loss may also occur over a long period of time (chronic bleeding):

• Heavy menstruation
• Bleeding cancer or polyps (benign growths) in the gut
• Bleeding gastric or duodenal ulcers
• Nosebleeds
• Bleeding haemorrhoids (piles)

Increased destruction of red blood cells occurs in hereditary conditions in which either
the haemoglobin molecules or the red cells themselves are abnormal:

• Thalassaemia (abnormal haemoglobin)

• Sickle cell disease (abnormal haemoglobin)
• Hereditary spherocytosis (abnormally shaped red cells)
• Hereditary elliptocytosis (abnormally shaped red cells)
• G6PD deficiency (lack of an enzyme in red cells)

These hereditary conditions are fairly common throughout the world but different types
are more common in different races.

Increased destruction of red blood cells also occurs in conditions in which the immune
system produces antibodies (molecules normally produced to kill bacteria and viruses)
that bind to and destroy red cells. This is called 'autoimmune haemolytic anaemia' and
many people with this type of anaemia have an underlying condition such as an infection,
primary autoimmune disease or leukaemia. Any condition in which the spleen is enlarged
also causes destruction of red cells.

Symptoms and complications of anaemia

The symptoms will depend on the severity of the anaemia. Pallor (a pale complexion) is a
poor indication of the degree of anaemia. If the excessive bleeding is chronic, such as
from a stomach ulcer or heavy periods, there may be no symptoms at all or there may be:

• Tiredness
• Faintness
• Dizziness (especially when standing)

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If the blood loss is more severe or more rapid (as in an accident) there may be:

• Thirst
• Sweating
• Severe fatigue
• Breathlessness
• Chest pain
• Heart attack
• Stroke (due to lack of oxygen to the brain)

In people who have increased red cell destruction, the breakdown products of
haemoglobin may cause jaundice (a yellow colouring of the skin and eyes).

Sickle Cell Anaemia

Sickle Cell Anaemia affects the shape of red blood cells,

changing them from a flattened disc to a sickle or crescent shape.
Whereas normal red blood cells are smooth and move easily
through blood vessels, sickle blood cells are hard, inflexible and
tend to clump together, causing them to get stuck in blood vessels
as blood clots, thereby blocking the flow of blood. This can cause
pain, blood vessel damage and a low red blood cell count (anaemia)
A sickle cell next due to the more fragile nature of sickle blood cells. The abnormal
to regular red sickle shape is due to the presence of abnormal haemoglobin
blood cells (haemoglobin S), which contains abnormal beta polypeptide with a
single amino acid substitution at position 6 along the polypeptide
chain (the alpha chain is normal). The abnormal chain reduces the amount of oxygen
inside the red blood cell, altering its shape.

Heterozygotes, where one beta chain gene is affected and the other is normal,
usually display normal red blood cells, and it is only when both beta chain genes are
affected (homozygote) that the sickle cell disease is seen. However, heterozygote carriers

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of the disease are better protected against malaria than people with two normal beta chain
genes. This malarial protection has caused the sickle cell gene to reach high levels in
indigenous populations in Africa and India.

Thalassaemia

Thalassaemia is caused when the production of haemoglobin chains is impaired,

the most common forms affecting the alpha globin chain (alpha Thalassaemia) or the beta
globin chain (beta Thalassaemia). The chains themselves can be normal, but the amounts
produced are not; sometimes the genes can even be missing. There are four genes needed
to make the alpha globin chain, with moderate to severe anaemia resulting when more
than two genes are affected. With the beta globin chain there are two genes required, the
most severe form of the disease affecting both genes. An equal number of alpha and beta
globin proteins are required to make functional adult haemoglobin, and a deficiency in
either chain will cause an imbalance that damages and destroys red blood cells, thereby
producing anaemia. The deficiency in globin chains can cause the an abnormal
association of globin chains: in the case of alpha Thalassaemia, beta globin chains
combine to produce abnormal beta tetramers that cannot bind oxygen, whereas with beta
Thalassaemia no such alpha tetramers exist – instead the alpha globin chains become
degraded in the absence of beta globin chains.

Porphyria

Porphyria disorders affect the production of functional haem molecules in

haemoglobin. The haem component is composed of a porphyrin ring complex and iron.
Porphyria affects the production of a functional porphyrin complex through a genetic
mutation at any one of the many enzymatic steps involved in its production. While most
haem is in the blood associated with haemoglobin, haem is also required for in several
other tissues, including the liver. Porphyrias can affect either the skin (cutaneous
porphyria) or the nervous system (acute porphyria). Cutaneous porphyria causes the
development of blisters, itching and swelling upon exposure to light, while acute
porphyria causes pain, numbness, paralysis or mental disorders.

Certain light-sensitive drugs have been developed based on the abnormal

porphyrin structures that result from cutaneous porphyria. These drugs have been used to
treat cancer: cancer cells preferentially absorb these porphyrin-like structures and help to
destroy the cancer cells upon exposure to light treatment involving lasers.

Carbon Monoxide Poisoning

Carbon monoxide (CO) binds to haemoglobin with a higher affinity (200x

greater) than oxygen, and at the same binding site. Consequently, carbon monoxide will
bind haemoglobin preferentially over oxygen when both are present in the lungs - even
small amounts of carbon monoxide can dramatically reduce the ability of haemoglobin to
transport oxygen. Levels as low as 0.02% carbon monoxide can cause headaches and

40
nausea, while a concentration of 0.1% can lead to unconsciousness. This accounts for the
suffocation caused by carbon monoxide fumes, such as from the exhaust of a car engine.
People who smoke heavily can block up to 20% of the oxygen binding sites in
haemoglobin with carbon monoxide. When carbon monoxide binds to haemoglobin it
becomes a very bright cherry red (carboxyhaemoglobin), giving the person the
appearance of a ‘healthy glow’.

By contrast, carbon dioxide (CO2), which is produced as a waste product after

aerobic respiration, binds to haemoglobin at a different site, therefore does not compete
with oxygen for binding to haemoglobin.

Mutations in the globin chain are associated with the hemoglobinopathies, such as
sickle-cell disease and thalassemia.

There is a group of genetic disorders, known as the porphyrias that are characterized by
errors in metabolic pathways of heme synthesis. King George III of the United Kingdom
was probably the most famous porphyria sufferer.

To a small extent, hemoglobin A slowly combines with glucose at a certain location in the
molecule. The resulting molecule is often referred to as Hb A1c. As the concentration of
glucose in the blood increases, the percentage of Hb A that turns into Hb A1c increases. In
diabetics whose glucose usually runs high, the percent Hb A1c also runs high. Because of
the slow rate of Hb A combination with glucose, the Hb A1c percentage is representative
of glucose level in the blood averaged over a longer time (the half-life of red blood cells,
which is typically 50-55 days).

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