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Haemoglobin synthesis &
catabolism
Dr. Suhair Abbas Ahmed
Haemoglobin synthesis
The haemoglobins are red globular proteins,
which have a molecular weight of about
68,000 and comprise almost one third of
the weight of a red cell.
The haemoglobin is composed of haem and
globin.
Haemoglobin synthesis
 The main function of red cells is to carry O2
to the tissues and to return carbon dioxide
(CO2) from tissues to the lungs.
 In order to achieve this gaseous exchange
the red cells contain the specialized protein
haemoglobin.
 Each red cell contains approximately 640
million Hb molecules.
Haemoglobin synthesis
 65% of the Hb is synthesized in the erythroblasts,
and 35% at the reticulocyte stage.
 Haem synthesis occurs largely in the
mitochondria.
 Globin synthesis occurs in the polyribosomes.
 Although haem and globin synthesis occur
separately within developing red cell precursors,
their rates of synthesis are carefully coordinated to
ensure optimal efficiency of Hb assembly.
Globin synthesis
 The various globins that combine with haem to
form Hb are all single chain polypeptides.
 The synthesis of these globins is under genetic
control.
 Humans normally carry eight functional globin
chains, arranged in two, duplicated gene clusters:
the b-like cluster (b, g, d and e globin genes) on the
short arm of chromosome 11 and the a-like cluster
(a and z globin genes) on the short arm of
chromosome 16.
Ontogeny of globin synthesis
Globin synthesis is first detected in the primitive
erythroid precursors of the yolk sac at about 3
weeks’ gestation.
 Embyonic :
Haemoglobin Gower I ( z2e2)
Haemoglobin Portland ( z2g2)
Haemoglobin Gower II (a2e2)
 Fetal : HbF (a2g2), HbA (a2b2)
 Adult : HbA, HbA2 ( a2d2), HbF.
Haemoglobin
 Each molecule of
normal adult
haemoglobin (Hb-A)
consists of four
polypeptide chains
a2b2, each with its own
haem group.
Haemoglobin
 Normal adult blood also contains small
quantities of two other haemoglobins, Hb-F
and Hb-A2. These also contain a chains but
with g and d chains respectively instead of b.
 The major switch from fetal to adult
haemoglobin occurs 3-6 months after birth.
Normal Hb in adult blood
Hb A
Hb A2
Hb F
structure
a2b2
a2d2
a2g2
Normal %
96-98 %
1.5-3.2 %
0.5-0.8 %
Haemoglobin synthesis
 Haem synthesis starts with
the condensation of
glycine and succinyl
coenzyme A under the
action of a rate limiting
enzyme d-aminolaevulinic
acid synthase.
 d-ALA will be formed.
 Pyridoxal phosphate (vit.
B6) is a coenzyme for this
reaction.
Haemoglobin synthesis
 A series of biochemical
reactions will follow.
 Two molecules of d-ALA
condense to form a pyrrole
called porphobilinogen
(PBG)
 Four PBG condense to
form a tetrapyrrole
uroporphyrinogen III.
 UPG III is then converted
to coproporphyrinogen.
Haemoglobin synthesis
 CPG then changes to
protoporphyrin which
ultimately combines with
iron in the ferrous state
(Fe2+) to form haem.
 Iron is brought to the
developing red cells by a
carrier protein ( transferrin)
which attaches to special
binding sites on the
surface of these cells.
 Transferrin releases iron
and returns back to
circulation.
Haemoglobin synthesis
 Each molecule of
haem combines with a
globin chain.
 A tetramer of four
globin chains each
with its own haem
group in a pocket is
formed to make up a
haemoglobin molecule.
Haemoglobin structure
 Haem consists of a
protoporphyrin ring with an
iron atom at its centre.
 The protoporphyrin ring
consists of four pyrrole
groups which are united by
methane bridges (=C-).
 The hydrogen atoms in the
pyrrole groups are
replaced by four
methylene (CH3-), two
vinyl (-C=CH2) and two
propionic acid (-CH2-CH2COOH) groups.
Haemoglobin catabolism
*normal red cell destruction*
 Red cell destruction usually occurs after a mean
life span of 120 days.
 The cells are removed extravascularly by
macrophages of the reticuloendothelial system
(RES), specially in the bone marrow but also in the
liver and spleen.
 Red cell metabolism gradually deteriorates as
enzymes are degraded and not replaced, until the
cells become non viable, but the exact reason why
the red cells die is obscure.
Haemoglobin catabolism
*normal red cell destruction*
 The breakdown of red cells liberates
1- iron for recirculation via plasma transferrin
to marrow erythroblasts
2- protoporphyrin which is broken down to
bilirubin.
3- globins which are converted to amino
acids.
Normal red cell destruction
- The bilirubin circulates to the liver where it is
conjugated to glucuronides which are
excreted into the gut via bile and converted
to stercobilinogen and stercobilin(excreted
in faeces).
- Stercobilinogen and stercobilin are partly
reabsorbed and excreted in urine as
urobilinogen and urobilin.
Normal red cell destruction
 A small fraction of protoporphyrin is
converted to carbon monoxide (CO) and
excreted via the lungs.
 Globin chains are broken down to amino
acids which are reutilized for general protein
synthesis in the body.
Normal red cell breakdown
haemoglobin
haem
iron
transferrin
globin
protoporphyrin
CO
Expired air
Amino acids
Bilirubin
(free)
Liver
conjugation
erythroblast
Bilirubin glucuronides
Urobilin(ogen)
Urine
Stercobilin(ogen)
faeces
Haemoglobin abnormalities
There are mainly two types of abnormalities,
these are :
 Quantitative abnormalities: where there is
reduction in the production of certain types
of globins e.g. a thalassaemia
b thalassaemia
 Qualitative abnormalities: where there is
production of abnormal haemoglobin e.g.
sickle cell anaemia.