Lecture 2

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HAEMOGLOBIN SYNTHESIS

Ms. Ruth Takyi (MLS)


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BSc, MPhil
OBJECTIVES
 Introduction

 Heme Synthesis

 Globin synthesis

 Dyshaemoglobin

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INTRODUCTION
 In 1862, Felix Seyler identified the respiratory protein
haemoglobin

 He discovered the characteristic color spectrum of


haemoglobin and proved that this was the true colouring matter
of the blood

 Following this discovery, research began on the reaction of


haemoglobin with oxygen

 Today, the activities of haemoglobin and oxygen are well-


known

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INTRODUCTION
 Haemoglobin (Hb) is one of the most studied proteins in the
body

 It comprises approximately 95% of the cytoplasmic content of


RBCs

 The body very efficiently carries haemoglobin in RBCs, which


provides protection from denaturation in the plasma and loss
through the kidneys

 Free (non-RBC) haemoglobin, generated from RBCs through


haemolysis, has a short half-life outside of the RBCs

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INTRODUCTION
 Free Hb when released into the plasma, is rapidly salvaged to
preserve its iron and amino acid components

 When salvage capacity is exceeded, it is excreted by the kidneys

 Haemoglobin’s main function is to transport oxygen from the


lungs to tissues and transport carbon dioxide from the tissues to
the lungs for exhalation

 It also transports nitric oxide (NO), a regulator of vascular tone

 Haemoglobin also contributes to acid-base balance by binding


and releasing hydrogen ions
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INTRODUCTION
 Normal adult haemoglobin A is inherited in simple mendelian
fashion, the genotype for this phenotype is A/A

 Abnormalities of haemoglobin types may be seen in various


haematological disorders

 Related to either amino acid substitutions or diminished


production of one of the polypeptide chains

 These disorders are referred to as hemoglobinopathies

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BIOSYNTHESIS OF
HAEMOGLOBIN
 Haemoglobin is synthesized during most of the erythrocytic
maturation process

 Approximately 65% of cytoplasmic haemoglobin is


synthesized before the nucleus is extruded

 The remaining 35% is synthesized in the early reticulocyte

 The major components of haemoglobin are heme and globin

 The synthesis of heme is a complex process that involves


multiple enzymatic steps
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HEME SYNTHESIS
 The process begins when succinylcoenzyme A (CoA) condenses
with glycine to form delta-aminolevulinic acid (ALA)

 This initial condensation reaction occurs in the mitochondria

 The most important limiting step in this reaction is the rate of


conversion to delta-ALA, which is catalyzed by the enzyme ALA
synthetase

 The activity of this enzyme is influenced by both erythropoietin


and by the presence of the cofactor pyridoxal phosphate (vitamin
B6)
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HEME SYNTHESIS
 The synthesis reaction continues in the cytoplasm

 Two molecules of ALA condense to form the monopyrrole


porphobilinogen (PBG)

 This reaction is catalyzed by the enzyme ALA dehydrase

 Four molecules of PBG condense into a cyclic tetrapyrrole to


form uroporphyrinogen I or III

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HEME SYNTHESIS
 The type III isomer is converted to coproporphyrinogen III
(CPG) by decaboxylation ( All acetyl groups of UPG are
converted to methyl groups)

 CPG is acted upon in the mitochondria by CPG oxidase which


decarboxylate and oxidizes two propionic side chains to vinyl
groups

 Protoporphyrinogen IX thus formed and further oxidized to


protoporphyrin IX

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HEME SYNTHESIS
 The final steps, carried out in the mitochondria

 Involves the incorporation of iron to form heme

 Four of the six ordinate positions of ferrous (Fe2+) iron are


chelated to protoporphyrin by the enzyme heme synthetase
ferrochelatase

 This step completes the formation of heme

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HEME STRUCTURE
 Heme consists of a ring of carbon, hydrogen, and nitrogen
atoms called protoporphyrin IX

 With a central atom of divalent ferrous iron

 Each of the four heme groups is positioned in a pocket of the


polypeptide chain near the surface of the haemoglobin molecule

 The ferrous iron in each heme molecule reversibly combines


with one oxygen molecule

 When the ferrous irons are oxidized to the ferric state, they no
longer can bind oxygen. Oxidized haemoglobin is also called
methemoglobin
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14 Heme structure
INTRODUCTION TO GLOBIN
BIOSYNTHESIS
 Six structural genes code for six globin chains.

 The alpha (α) and zeta (δ) globin genes are on the short
arm of chromosome 16; the epsilon (ε), gamma (γ), delta
(δ), and beta (β) globin gene cluster is on the short arm of
chromosome 11

 The production of globin chains takes place in erythroid


precursors from the pronormoblast through the circulating
polychromatic erythrocyte, but not in the mature
erythrocyte

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GLOBIN BIOSYNTHESIS
 Transcription of the globin genes to messenger ribonucleic acid
(mRNA) occurs in the nucleus, and translation of mRNA to the
globin polypeptide chain occurs on ribosomes in the cytoplasm

 Although transcription of the α-globin genes produces more


mRNA than the β-globin gene, there is less efficient translation
of the α-globin mRNA

 Therefore, the α and β chains are produced in approximately


equal amounts.

 After translation is complete, the chains are released from the


ribosomes in the cytoplasm.

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GLOBIN BIOSYNTHESIS
 After their release from ribosomes, each globin chain
binds to a heme molecule, then forms a heterodimer

 The non-α chains have a charge difference that


determines their affinity to bind to the α chains

 The α chain has a positive charge and has the highest


affinity for a β chain due to its negative charge

 The γ-globin chain has the next highest affinity, followed


by the δ-globin chain

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GLOBIN BIOSYNTHESIS
 Two heterodimers then combine to form a tetramer. This
completes the haemoglobin molecule

 Two α and two β chains form Hb A, the major


haemoglobin present from 6 months of age through
adulthood

 There are 141 amino acids in each of the alpha chains


and 146 amino acids in each of the beta chains

 Hb A2 contains two α and two δ chains

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GLOBIN BIOSYNTHESIS
 Owing to a mutation in the promoter region of the δ-globin
gene, production of the δ chain polypeptide is very low

 Consequently, Hb A2 comprises less than 3.5% of total


haemoglobin in adults

 Hb F contains two α and two γ chains. In healthy adults, Hb F


comprises 1% to 2% of total haemoglobin, and it is present only
in a small proportion of the RBCs (uneven distribution)

 Both the structure and the production of globin in the


haemoglobin molecule are under genetic control

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ONTOGENY
 Haemoglobin composition differs with prenatal gestation
time and postnatal age

 Haemoglobin changes reflect the sequential activation and


inactivation (or switching) of the globin genes, progressing
from the δ to the α globin gene on chromosome 16 and
from the ε to the γ, δ, and β globin genes on chromosome
11

 The δ and ε globin chains normally appear only during the


first 3 months of embryonic development

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ONTOGENY
 These two chains, when paired with the α and γ chains,
form the embryonic haemoglobins

 During the second and third trimesters of fetal life and at


birth, Hb F (α2β2) is the predominant haemoglobin

 By 6 months of age and through adulthood, Hb A (α2β2)


is the predominant haemoglobin, with small amounts of
Hb A2 (α2δ2) and Hb

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Haemoglobin: a tetramer of four globin polypeptide chains, with
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DYSHEMOGLOBINS
 Dyshaemoglobins (dysfunctional haemoglobins that are
unable to transport oxygen) include methaemoglobin,
sulfhaemoglobin, and carboxyhaemoglobin

 Dyshaemoglobins form and may accumulate to toxic


levels, after exposure to certain drugs or environmental
chemicals or gasses

 The offending agent modifies the structure of the


haemoglobin molecule, preventing it from binding oxygen

 Most cases of dyshaemoglobinemia are acquired; a small


fraction of methaemoglobinemia cases are hereditary.
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METHEMOGLOBIN
 Methaemoglobin cannot carry oxygen because the oxidized
ferric iron cannot bind it

 An increase in the methaemoglobin level results in decreased


delivery of oxygen to the tissues

 Individuals with methaemoglobin levels less than 25% are


generally asymptomatic

 If the methaemoglobin level increases to more than 30% of


total haemoglobin, cyanosis (bluish discoloration of skin and
mucous membranes) and symptoms of hypoxia (dyspnea,
headache) occur

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METHEMOGLOBIN
 Levels of methemoglobin greater than 50% can lead to
coma and death

 An increase in methaemoglobin, called


methaemoglobinemia, can be acquired or hereditary

 The acquired form, also called toxic methaemoglobinemia,


occurs in normal individuals after exposure to an
exogenous oxidant, such as nitrites, primaquine, dapsone,
or benzocaine

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METHEMOGLOBIN
 As the oxidant overwhelms the haemoglobin reduction
systems, the level of methaemoglobin increases

 The patient may then exhibit cyanosis and symptoms of


hypoxia

 In many cases, withdrawal of the offending oxidant is


sufficient for a recovery

 However, if the level of methaemoglobin increases to 30%


or more of total haemoglobin, intravenous methylene blue
is administered
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SULFHEMOGLOBIN
 Sulfhemoglobin is formed by the irreversible oxidation of
haemoglobin by drugs (such as sulfonilamides,
phenacetin, nitrites, and phenylhydrazine) or exposure to
sulfur chemicals in industrial or environmental settings

 It is formed by the addition of a sulfur atom to the pyrrole


ring of heme and has a greenish pigment

 Sulfhemoglobin is ineffective for oxygen transport, and


patients with elevated levels present with cyanosis

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SULFHEMOGLOBIN
 Sulfhemoglobin cannot be converted to normal Hb A; it
persists for the life of the cell.

 Treatment consists of prevention by avoidance of the


offending agent

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CARBOXYHEMOGLOBIN
 Carboxyhemoglobin (COHb) results from the combination
of carbon monoxide (CO) with heme iron

 The affinity of carbon monoxide for haemoglobin is 240


times that of oxygen

 Once one molecule of carbon monoxide binds to


haemoglobin, it shifts the haemoglobin-oxygen dissociation
curve to the left

 Carbon monoxide has been termed the silent killer because


it is an odorless and colorless gas, and victims may quickly
become hypoxic
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CARBOXYHEMOGLOBIN
 Some carboxyhemoglobin is produced endogenously, but
it normally comprises less than 2% of total haemoglobin

 Exogenous carbon monoxide is derived from the exhaust


of automobiles, tobacco smoke, and from industrial
pollutants, such as coal, gas, and charcoal burning

 In smokers, COHb levels may be as high as 15%

 As a result, smokers may have a higher hematocrit to


compensate for the hypoxia
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Assignment 2 – 10marks
Discuss briefly the oxygen dissociation curve and its application
in haematology
Instruction
Submission date: Next face-to-face (2 weeks)
4th July (Group A)
5th July (Group B)
11th July (Evening)

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