HB Synthesis and Catabolism

SAMUEL K.
APPIAH
• Office: SAHS - Rm. SF19
• Contact: 0245900367
• Email: [email protected]
Introduction To Haemoglobin
Haemoglobin is a tetramer of globin chains folded
around four heme groups.
It weighs ~ 64500D.
Composition
• 2 alpha
• 2 non- alpha globin chains.
•Heme = 10%
•Globin= 90%
•Heme's central iron atom binds one O2

•Each Hb molecule can transport four O2
•Each RBC contains 250 million Hb molecules
Structure of hemoglobin.
 Globin chains
Heme
group
 Globin chains
Hemoglobin consists of globin (two alpha and two beta Iron-containing heme pigment.
polypeptide chains) and four heme groups.
Haemoglobin Function
• The function of the Haemoglobin molecule

is to pick up oxygen in the lung and deliver
it to the tissues utilizing none of the
oxygen along the way.
• Hb structure is capable of pulling CO2
away from the tissues, as well as keeping
the blood in a balanced pH.
Genetic Control Of Human Haemoglobin
Hb Gower II (α2 ɛ2)
Hb Portland I (ζ 2 γ2)
02/22/22 3mths 3-6mths >6mths

Other Haemoglobins in normal adults
Hemoglobin Structure %
A α2 β2 92%
A2 α2 δ2 2.5%
A1C α2 (β-N-glucose) 3%
F α2 γ2 <1%
Gower-1 ζ2 ε2 0*
Gower-2 α2 ε2 0*
Portland ζ2 γ2 0*
* Indicates early embryonic form not seen in adults
Haemoglobin Synthesis
• Haem synthesis occurs largely in the mitochondria
• Step 1
1. Heme synthesis begins with condensation of glycine &
succinyl-CoA, with decarboxylation, to form -
aminolevulinic acid (ALA). –occurs in mitochondria
• Pyridoxal phosphate (vitamin B6) is a coenzyme for this
reaction.
ALA Synthase is the committed step & is usually rate-limiting
for the overall pathway..
Heme functions as a feedback inhibitor, repressing transcription

of the ALA Synthase gene in most cells
Lead can inhibit ALA synthase

Step 2
★ The succeeding few reactions occur in the cytoplasm.
one ALA condenses with another molecule of ALA to form
porphobilinogen(PBG).
★ the condensation involves removal of 2 molecules of water and the
enzyme is ALA dehydratase .
Step 3
The porphyrin ring is formed by condensation of 4 molecules of
porphobilinogen.
Porphobilinogen Deaminase catalyzes successive PBG condensations,
initiated in each case by elimination of the amino group.
Step 4
Uroporphyrinogen III Synthase converts the linear tetrapyrrole
hydroxymethylbilane to the macrocyclic uroporphyrinogen III.
 Step 5
 Uroporphyrinogen III converted to coproporphyrinonogen III
 enzyme: Uroporhpyrinogen III decarboxylase
- transported back into mitochondria
 Step 6
- coproporphyrinonogen is converted to protoporphyrinogen IX,
then to protoporphyrin IX
- enzyme: coproporphyrinonogen oxidative decarboxylase
- occurs in mitochondria
 Step 7
Heme is formed by incorporation of iron (Fe+2) by enzyme
ferrochelatase
- partly spontaneous
- ferrochelatase enhances rate
- also inhibited by lead
URO
COPRO
PROTO
Haemoglobin Synthesis
Summary
1. Major sites of heme synthesis liver and bone marrow
(erythroblasts).
2. Matured red blood cells have no mitochondria, so can’t
synthesize heme.
3. The substrates mainly include succinyl-CoA, glycine,
Fe2+ .
3. First and last 3 reactions take place in mitochondria,
others in cytoplasm
OXYGEN DISSOCIATION CURVE (OD
CURVE)
RBCs in systemic arterial blood carry O2 from
lungs to the tissues and return in venous blood
with CO2 to the lungs.
As the haemoglobin molecule loads and

unloads O2 the individual globin chains move
on each other. (Allosteric changes)
Allosteric changes cause Hb molecule to appear
in a tense and a relaxed form
When O2 is unloaded the β chains are pulled apart (tense),
permitting entry of the metabolite 2,3‐DPG resulting in a lower
affinity of the molecule for O2.
When oxygenated, the relaxed form is in place; 2,3-DPG is expelled
The binding and release of oxygen from the haemoglobin molecule are
defined by the oxygen dissociation curve (OD curve)
OXYGEN DISSOCIATION CURVE (OD
CURVE) CONT.
 The binding and release of O2 from Hb is responsible for the
sigmoid form of the haemoglobin O2 dissociation curve.
 There is a progressive increase in the percentage of the Hb that

is bound with oxygen as the blood PO2 increases.
 In the lungs in which the blood PO2 is 100 mm Hg, Hb is 97%

saturated with oxygen.
 In venous circulation, in which the PO2 is 40 mm Hg, 75% of the

Hb molecule is saturated with oxygen and 25% of the oxygen is
capable of being released when the Hb level is normal
Oxygen Dissociation Curve.
 In the normal curve (blue)
at 40 mm Hg, 75% of the
Hb molecule is saturated
Low
with oxygen, leaving 25% 2,3‐DPG
capable of being released to High
H+ 2,3‐
tissue. CO2 DPG
Temp H+
 Note the right-shifted CO2
curve (red). At 40mm Hg, Temp
Hb is 50% saturated but
willing to give up 50% of
its oxygen to the tissues.
 Note the left-shifted curve

(green). At 40 mm Hg, Hb
is 85% saturated but
willing to release only 12%
to the tissues.
Other Factors Influencing Haemoglobin
Saturation
• Temperature, H+, PCO2, and BPG:
– Modify the structure of haemoglobin and alter its
affinity for oxygen
– Increase in the factors:
• Decrease haemoglobin’s affinity for oxygen
• Enhance oxygen unloading from the blood
– Decreases act in the opposite manner
• These parameters are all high in systemic
capillaries where oxygen unloading is the goal
Factors That Increase Release of
Oxygen by Hb
• As cells metabolize glucose, carbon dioxide is
released into the blood causing:
– Increases in PCO2 and H+ concentration in capillary blood
– Declining pH (acidosis) weakens the haemoglobin-
oxygen bond (Bohr effect)
• Metabolizing cells have heat as a byproduct and
the rise in temperature increases BPG synthesis
• All these factors insure oxygen unloading in the
vicinity of working tissue cells
FATE OF RED BLOOD CELLS
 Life span in blood stream is 60-120 days
 RBCs are phagocytosed and/or lysed
Normally, lysis occurs extravascularly in the

reticuloendothelial system subsequent to RBC
phagocytosis
 Lysis can also occur intravascularly (in blood

stream)
Extravascular & Intravascular Pathways for
RBC Destruction
a). Normal RBC destruction takes place extravascularly in Macrophages.

b). Intravascular haemolysis occurs in some pathological disorders
NORMAL BILIRUBIN  Uptake of bilirubin by the liver is mediated
METABOLISM by a carrier protein (receptor)
 On the smooth ER, bilirubin is conjugated

with glucoronic acid
 Glucoronic acid is the major conjugate -

catalyzed by UDP glucuronyl tranferase
“Conjugated” bilirubin is water soluble and is

secreted by the hepatocytes into the biliary
canaliculi
 Converted to stercobilinogen (urobilinogen)

(colorless) by bacteria in the gut
 Oxidized to stercobilin which is colored
 Excreted in feces
 Some stercobilin may be re-adsorbed by

the gut and re-excreted by either the liver or
kidney
Prehepatic (haemolytic) jaundice
• Results from excess
production of bilirubin (beyond
the livers ability to conjugate
it) following hemolysis
• Excess RBC lysis is commonly

the result of autoimmune
disease; haemolytic disease of
the newborn (Rh- or ABO-
incompatibility); structurally
abnormal RBCs (Sickle cell
disease).
• High plasma concentrations of

unconjugated bilirubin (normal
concentration ~0.5 mg/dL)
Intrahepatic jaundice
• Impaired uptake,
conjugation, or secretion
of bilirubin
• Reflects a generalized
liver (hepatocyte)
dysfunction
• In this case,
hyperbilirubinemia is
usually accompanied by
other abnormalities in
biochemical markers of
liver function
Post-hepatic jaundice
• Caused by an obstruction of the
biliary tree
• Plasma bilirubin is conjugated,

and other biliary metabolites,
such as bile acids accumulate in
the plasma
• Characterized by pale colored

stools (absence of fecal
bilirubin or urobilin), and dark
urine (increased conjugated
bilirubin)
• In a complete obstruction,
urobilin is absent from the
urine

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HB Synthesis and Catabolism

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SAMUEL K.

•Heme's central iron atom binds one O2

• The function of the Haemoglobin molecule

Hb Gower II (α2 ɛ2)

02/22/22 3mths 3-6mths >6mths

Heme functions as a feedback inhibitor, repressing transcription

Lead can inhibit ALA synthase

As the haemoglobin molecule loads and

 There is a progressive increase in the percentage of the Hb that

 In the lungs in which the blood PO2 is 100 mm Hg, Hb is 97%

 In venous circulation, in which the PO2 is 40 mm Hg, 75% of the

 Note the left-shifted curve

 Life span in blood stream is 60-120 days

 RBCs are phagocytosed and/or lysed

Normally, lysis occurs extravascularly in the

 Lysis can also occur intravascularly (in blood

a). Normal RBC destruction takes place extravascularly in Macrophages.

 On the smooth ER, bilirubin is conjugated

 Glucoronic acid is the major conjugate -

“Conjugated” bilirubin is water soluble and is

 Converted to stercobilinogen (urobilinogen)

 Oxidized to stercobilin which is colored

 Some stercobilin may be re-adsorbed by

• Excess RBC lysis is commonly

• High plasma concentrations of

• Plasma bilirubin is conjugated,

• Characterized by pale colored

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