The document discusses hemoglobin synthesis, which consists of two parts: globin synthesis and heme synthesis. Globin is synthesized through transcription and translation of genes on chromosomes 16 and 11. Heme is synthesized through the Shemin cycle, where glycine and succinyl-CoA are condensed to form delta-aminolevulinic acid, which undergoes further modifications to ultimately form protoporphyrin IX. Protoporphyrin then binds iron to form heme. Heme synthesis is regulated by feedback inhibition of delta-aminolevulinic acid synthase, and both heme and globin are required for the formation of functional hemoglobin.

1. BY
DR EBOT WALTER OJONG
HEMOGLOBIN SYNTHESIS

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3. INTRODUCTION
 Hemoglobin is an oxygen-binding protein found in
erythrocytes that transports oxygen from the lungs to tissues.
 Each hemoglobin molecule is a tetramer made of four
polypeptide globin chains.
 Hemoglobin (average molecular weight 64,000) consists of
heme (iron and protoporphyrin) and globin (two polypeptide
chains).
 Haem & globin produced at two different sites in the cells.
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4. INTRODUCTION
The iron molecule in each heme moiety can bind
and unbind oxygen, allowing for oxygen transport
in the body.
The most common type of hemoglobin in the adult
is HbA, which comprises two alpha-globin and two
beta-globin subunits.
Different globin genes encode each type of globin
subunit.
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5. INTRODUCTION
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6. INTRODUCTION
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7. INTRODUCTION
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8. INTRODUCTION
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9. INTRODUCTION
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10. INTRODUCTION
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11. INTRODUCTION
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12. INTRODUCTION
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13. INTRODUCTION
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14. MECHANISM OF ACTION OF HAEMOGLOBIN BUFFER SYSTEM
(KHb/H Hb and KHbO2/HHbO2)
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15. INTRODUCTION
Porphyrins are a class of water-soluble,
nitrogenous biological pigments (biochromes),
derivatives of which include the hemoproteins.
A class of pigments (including haem and
chlorophyll) whose molecule contain a flat ring of
four linked heterocyclic groups, with a central
metal atom.
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16. STRUCTURE OF PORPHYRINS
Porphyrins are cyclic compounds (complex cyclic
compounds).
Each porphyrin molecule is made up of four
pyrrole rings.
Each pyrrole ring is a five membered close
structure containing four carbon atoms and one
nitrogen.
The rings are linked by methylene (=HC-) bridge.
Porphyrins are found in heme and chlorophyll.
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17. STRUCTURE OF PORPHYRINS
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21. SYNTHESIS OF PORPHYRINS (SHEMIN CYCLE)
Shemin cycle (also called glycine-succinate cycle).
A series of metabolic steps in which glycine is
condensed with succinyl-CoA and is then oxidised
to CO2 and H2O with regeneration of the succinyl–
coA; important in the synthesis of d-
aminolevulinic acid and in the metabolism of red
blood cells.
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22. SYNTHESIS OF PORPHYRINS (SHEMIN CYCLE)
The committed step for porphyrin biosynthesis is the
formation of δ-aminolevulinic acid (δ-ALA, 5-ALA or
dALA) by the reaction of the amino acid glycine with
succinyl-CoA from the citric acid cycle.
Two molecules of dALA are then combined by
porphobilinogen synthase to give porphobilinogen
(PBG), which contains a pyrrole ring.
Four PBGs are then combined through deamination
into hydroxymethyl bilane (HMB), which is hydrolysed
to form the circular tetrapyrrole uroporphyrinogen III.
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23. SYNTHESIS OF PORPHYRINS (SHEMIN CYCLE)
This molecule undergoes a number of further
modifications.
Intermediates are used in different species to
form particular substances, but, in humans, the
main end-product protoporphyrin IX is combined
with iron to form heme.
Porphyrias arise as a result of deficiency of
enzymes in the biosynthetic pathway
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24. SYNTHESIS OF PORPHYRINS (SHEMIN CYCLE)
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26. SYNTHESIS OF
HEMOGLOBIN
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27. SYNTHESIS OF HEMOGLOIN
• Synthesis of hemoglobin actually starts in the
proerythroblastic stage.
• However, hemoglobin appears in the intermediate
noroblastic stage.
• Production of hemoglobin continues until the
stage of reticulocyte (65% at erythroblast stage
and 35% at reticulocyte stage).
• The heme portion of the hemoglobin is synthesized
in the mitochondria and the globin part is
synthesized in the ribosomes (cytosol).
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28. SYNTHESIS OF HEMOGLOIN
The two main components of hemoglobin
synthesis are globin production and heme
synthesis.
Globin chain production occurs in the cytosol
(polyribosomes) of erythrocytes and occurs by
genetic transcription and translation.
Many studies have shown that the presence of
heme induces globin gene transcription.
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29. SYNTHESIS OF HEMOGLOIN
Genes for the alpha chain are on chromosome 16,
and genes for the beta chain are on chromosome
11.
Heme synthesis occurs in both the cytosol and the
mitochondria of erythrocytes.
It begins with glycine and succinyl coenzyme A and
ends with the production of a protoporphyrin IX
ring.
The binding of the protoporphyrin to a Fe2+ ion
forms the final heme molecule.
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30. SYNTHESIS OF HEMOGLOIN
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31. SYNTHESIS OF HEMOGLOIN
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32. SYNTHESIS OF HEMOGLOIN
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33. HEME
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34. INTRODUCTION
 Heme is an iron containing porphyrin
 Heme is the prosthetic group of several proteins and enzymes like:
I. Hemoglobin: Important for oxygen transport
II. Myoglobin: Acts as a storage of oxygen in the tissues
III. Cytochromes: Plays important role in the electron transport chain
IV. Cytochrome P450: Important for detoxification of drugs in the liver
V. Catalase: Antioxidant enzyme
VI. Peroxidase: Antioxidant enzyme
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35. STRUCTURE OF HEME
Heme is formed from four pyrole rings joined
together with the help of methenyl bridges
The pyrole rings can be numbered in roman
numbers I, ii, iii, iv
The methenyl bridges can be numbered as alpha,
beta, gamma and delta
Type III porphyrin rings are commonly seen in
humnas
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36. STRUCTURE OF HEME
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38. SITE OF HEME SYNTHESIS
It takes place in all cells (except
mature RBCs).
To a major extent heme synthesis
takes place in the liver and bone
marrow.
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39. MAIN PATHWAY OF HEME SYNTHESIS
The first step in the synthesis of
heme occurs in the mitochodria and
it is the rate limiting step.
There is condensation of glycine with
succinyl-CoA (from the TCA cycle)
catalysed by ALA synthase (rate
limiting enzyme).
Deficiency of PLP leads to anaemia.
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40. MAIN PATHWAY OF HEME SYNTHESIS
The next step occurs in the cytosol.
ALA dehydratase and ferrochelatase are lead
sensitive enzymes(inhibited by lead).
Delta – ALA is detected in the urine of patients
suspected of having lead poisoning.
Coproporphyronogen-III enters the mitochondrion
where it is oxidatively decarboxylated to
protoporphyrinogen-IX.
Heme inhibits the first step of this pathway by
feedback inhibition.
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41. MAIN PATHWAY OF HEME SYNTHESIS
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42. REGULATION OF HEME SYNTHESIS
 Heme synthesis is mainly regulated by the rate limiting step
enzyme, ALA synthase.
 This enzyme is allosterically regulated with the help of heme
 Heme inhibits the transport of ALA synthase from the cytoplasm
into the mitochondrial matrix
 Heme decreases the translation of ALA Synthase
 It represses ALA synthase gene
 ALA synthase I enzyme in the hepatocytes is induced by drugs like
barbiturates, phenytoin etc.
 Availability of PLP is important for heme synthesis as deficiency will
lead to microcytic hypochromic anaemia
 ALA synthase I activity is increased during fasting and starvation
 ALA synthase II is regulated entirely by the availability of iron
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43. REGULATION OF HEME SYNTHESIS
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44. REGULATION OF HEME SYNTHESIS
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45. REGULATION OF HEME SYNTHESIS
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46. REGULATION OF HEME SYNTHESIS
 Carbohydrate diet and infusion of glucose reduces ALA synthase
activity because it works by PPAR alpha.
 ALA synthase exists in two forms, type I and type II. Type I ALA
synthase is present in all cells of the body but type II is present in
erythroid precursor cells. The gene for ALA synthase II is on X
chromosome
 Erythroid cells contribute 85% of heme synthesis
 The other 15% heme synthesis takes place in other tissues but
chiefly in the liver.
 Steroids and barbiturates will lead to the stimulation of
cytochrome P450. This will lead to stimulation of heme synthesis.
 The compartmentalisation of enzymes also plays an important role
in the regulation of heme biosynthesis.
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47. REGULATION OF HEME SYNTHESIS
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48. SYNTHESIS OF GLOBIN
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49. SYNTHESIS OF GLOBIN
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 The alpha and beta globin chains are made via the process of
protein synthesis. The information about these polypeptide
chains is present in the DNA of the red blood cells.
 The synthesis of the protein part of hemoglobin involves two
steps;
 Copying of the information present in the gene in the form of
messenger RNA. The mRNA copies of the gene are made by
RNA polymerase 2 in a process called transcription. Once the
mRNA molecule has undergone post-transcriptional changes,
it moves out of the nucleus into the cytoplasm of the cell.
Here, it is acted upon by the protein manufacturing
machinery of the cell.

50. SYNTHESIS OF GLOBIN
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 The second step involves translating the information
present in the mRNA to the sequence of amino acids in
the polypeptide chains. The codons on the mRNA are
read by the tRNA on the surface of the ribosomes and
complementary amino acids are added making a
polypeptide chain. Once a termination codon is reached,
the polypeptide chain is released from the translation
complex.
 The genes for alpha-globin chains are present on
chromosome 16 while those for beta-globin chains are
present on chromosome 11. There are two alpha genes
on chromosome 16 while only one beta gene is present
on chromosome 11.

51. SYNTHESIS OF GLOBIN
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52. SYNTHESIS OF GLOBIN
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53. SYNTHESIS OF GLOBIN
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• The alpha and beta chains formed by the above
process undergo further structural modifications.
• Normally, different types of hemoglobins are
present during embryonic life, fetal life, infancy,
and adulthood.
• Globin synthesis, starts at 3rd week of gestation

54. SYNTHESIS OF GLOBIN
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55. SYNTHESIS OF GLOBIN
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56. FACTORS REQUIRED FOR THE SYNTHESIS OF
HEMOGLOBIN
First class proteins i.e. proteins of high biological
value are necessary for Hb synthesis. e.g. Histidine,
Phynyl alanine, Leucine etc.
Vitamins : Vit B12, Vit C are helpful in synthesis.
Folic acid, riboflavin, nicotinic acid, pantothenic
acid play important role. Vit B12 and Folic acid are
called maturation factors and are required for
multiplication and maturation of RBC.
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57. FACTORS REQUIRED FOR THE SYNTHESIS OF
HEMOGLOBIN
Endocrine Secretions: Thyroid hormones are
required for synthesis.
Thyroxine is important.
Iron is required in ferrous state for synthesis of the
haem of Hb and deficiency of Fe causes
microcytic and hypocromic anemia.
Copper is required for biosynthesis of Hb.
Cobalt and Manganese is required in very small
quantities.
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58. FACTORS WHICH AFFECT HEMOGLOBIN LEVELS
Age
Sex
Diurnal variation
Altitude
Exercise
Excitement
Adrenaline
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