Transcript HEMOGLOBIN AACHROMO PROTEINCHROMO …

Hemoglobin
DR QAZI IMTIAZ RASOOL
OBJECTIVES
1. Describe the structure of hemoglobin molecu
2. Describe synthesis of hemoglobin in brief.
3. List the functions of hemoglobin.
4. Enlist various types of normal and abnormal
hemoglobin’s.
Hemoglobin
1. if the body had to depend upon
dissolved O2 in the plasma
to supply O2 to the cells
2.The heart would have
to pump 140 l/min instead
of 4-6 l/min.
3. RBC have nuclei during
early stages of development
mature to make room for Hb
HB
historical facts
1. 1st protein to be crystallized (1849);
2. 1st to be associated with a specific physiological
function (1875);
3. 1st proteins to have its molecular weight (64,500)
determined correctly (1920s);
4. 2nd protein having its 3-D structure determined (1969)
5. .Hb: A protein that you can “see” with your
naked eyes!
Synthesis:
following R essential
1.1st class proteins – milk, fish, egg, soyabean etc.
2. Metals – iron and sulphur.------copper+calcium
3. Vitamin B12 (Folic acid).-------cobalt
4. Porphyrin compound
Synthesis
1.- Erythroblasts, =65% ---7days—intermediate normoblast stag
- Reticulocyte stage=35% ------2 days
2. Haem synthesis in the mitochondria.
3. Globin synthesis in the polyribosomes
4. Although synthesis occur separately within developing red
cell precursors, their rates R coordinated for Hb assembly.
Haemoglobin
Chemistry: It is a chromo protein, mol:wt. 64000
1.Single RBC contains about 270 million HB molecules. Each RBC
can hold about 1 billion mol of O2. Hb =1/3 of the weight of RBC
2. Heme = porphyrin ring + Fe2
non-protein (pigment)
– Source of iron in body
– Iron – held in organic lattice
– Each iron holds 1 mol O2
3. Adult Hb Globin = 2 α + 2β chains
each with its own haem group
i.e. α1 β1 and α2 β2
Structure of Heme
1.a protoporphyrin ring with an iron atom at its centre
starts from a cyclic tetrapyrrole i.e. consists of 4 mol;
of pyrrole (mol:wt1600 X 4).
Pyrrole ring
2. - imparts a red color
3. -R,
-methyl (M),
-vinyl (V)
- proprionate (Pr) groups
Porphyrin Ring
1
Iron distribution
hemoglobin
feritin
myoglobin
3%
27%
70%
Iron
1. Food: Fe3+
absorbable Fe2+
`Gastric juice (gastroferrin)+ vit C reduces
2. Absorbed in duodenum
3. Fe2+ plasma level 10-35 mol/l
4.
5.
6.
7.
8.
Apoferritin (mucosa)
Transferrin ( Fe3+; plasma; β1-globulin),
Ferritin; spleen, liver, bone marrow; plasma ferritin,
hemosiderin
There is no physiological mechanism for the
excretion of excess iron
Iron metabolism
1. Iron is indipensable for life
(either in heme or non-heme form essential for oxygen
transport, electron transfer, DNA synthesis, etc.)
2.Iron is insoluble
([Fe] cannot exceed 10-17)
3. Iron is potentially toxic
(unless appropriately chelated, Fe plays a key role in the
formation of oxygen radicals)
1st : Haem synthesis
GENETIC ROLE
1.
2.
3.
Humans normally carry 8 functional globin genes, arranged in 2 duplicate
gene clusters:
These genes code for 6 different types of globin chains: α,β,γ,δ,ε,ζ, .
2 α (each with141 amino acids)
6. 2 β each - 146
Time
3 weeks of
Gestation
5 wks
Gestation
6-30 wks Gestation
30 wks Gestation
At Birth
Region
types
siage
t2e2
a2e2
embryonic
Portland
( z2g2)
embryonic
Hb F
a2g2
fetal, higher
Liver
Hb B
a2s2
adult,
2.5% Hb
B.M
Hb A
a2b2
adult Hb
Yolk Sac
Yolk-Sac
Liver & spleen
name
Gower I
Gower II
affinity to O2
Normal Hb in adult blood
Hb A
Hb A2
Hb F
structure
a 2b 2
a 2d 2
a 2g 2
Normal %
96-98 %
1.5-3.2 %
0.5-0.8 %
HbAIC: glycated Hb – important marker of longterm diabetes compensation
Haemoglobin catabolism
1. Destruction - life span- 120 days.
2. removed extravascularly by macrophages of the
reticuloendothelial system (RES),
- specially in the bone marrow
- but also in the liver and spleen.
3. cell metabolism deteriorates as enzymes R
degraded and not replaced, makes it non viable,
but the exact reason why the red cells die is
obscure.
HEMOGLOBIN BREAKDOWN
MACROPHAGE
HB breakdown
haemoglobin
haem
iron
transferrin
globin
protoporphyrin
CO
Expired air
Amino acids
Bilirubin
(free)
Liver
conjugation
erythroblast
Bilirubin glucuronides
Urobilin(ogen)
Urine
Enterohepatic cir
Stercobilin(ogen)
faeces
FUNCTIONS
1. - combines reversibly with O2 to form oxy-HB (HbO2)
.
2. combines + CO2 and transports 30% of total as(carbamino-HB)
3. Acts as a buffer
4. forms typical haem crystals with NaCl and glacial acetic acid
which is useful in diagnosis of blood sample (man or animal).
5. combines with other gases like CO, H2S ( poisoning ,death)
6.Nitric oxide (NO) binds to Hb, NO causing vasodilation to ↑ blood
flow and O2 delivery
Normal values
1. At birth: 23 gm%
2. Falls to 10.5gm% by 3 month (breast feed no iron)
3. Rises gradually to 12.5 rises at 1 year of age.
4. Males: 14 – 18 gm%
5. Females: 12 – 15 gm % females: 12 – 15 gm%
Differences
Hemoglobin
&
Myoglobin
1. Found in Blood
1. Found in Heart and
skeletal muscles
2. Composed of 4 Heme
and 4 Globin chains
2. Composed of 1 Heme
and 1 Globin chain
3. Carrier of Oxygen and
Carbon dioxide
3. Reservoir and Carrier of
Oxygen
4. Higher Oxygen affinity
4. Lesser Oxygen affinity
Myoglobin and Hb Structure
Glu6 Val6
oxyMb (MbO2)
deoxyMb
oxyHb (HbO2)
a
deoxyHb
O2
b
O2
O2
O2
b
O2
a
Glu6 Val6
CLASSIFICATION of ANEMIAS
Deficiency of Hb in the blood caused by either: RBC
Count or Hb in the RBCs
1.
Hemorrhagic anemiahemorrhagic anemia
2.
Aplastic anemiaaplastic anemia
3.
Megaloblastic anemiamegaloblastic anemia
4.
Pernicious anemiapernicious anemia
5.
Hemolytic anemiahemolytic anemia
6.
Sickle cell anemiasickle cell anemia
7.
Iron deficiency anemiairon deficiency anemia
8.
Secondary anemia (renal)secondary anemia (renal)
Anemia –
reduced O2 carrying capacity of the blood
• Insufficient hemoglobin content in RBCs:
Iron Deficiency - inadequate intake or absorption of iron.
Pernicious - dietary deficiency of Vitamin B12 or inadequate production of
intrinsic factor for absorption of Vitamin B12.
Abnormal hemoglobin
.
– Sickle Cell - one amino acid in the
287 forming the beta chains is wrong
In low O2 conditions the beta chains form stiff rods which
cause RBCs to sickle blocking small vessels.
Hb S
CAUSE:
1.
This disease is caused by a mutation in Hb.
(Abnormal polypeptides due to substitution of amino acids)
1.
Supression of synthesis of polypeptide chains.
2.
Occurs in 0.3 to 1 % of west african & american black
people
3.
Valine is substituted for glutamic acid at 6 position of beta
chain.
Red blood cells from sickle cell anemia patients: become
sickle-shaped only in the deoxygenated state!
Thalassemia
1. Defect in the synthesis of
either α & β
2. If the body doesn't produce
enough of either proteins,
the RBC cannot carry
sufficient O2.
3. - is anemia in early
childhood and lasts
throughout life.
Porphyria
1. abnormalities in the chemical steps production of heme
2. It is characterized by extreme sensitivity to light (exposure to sunlight causes vesicular erythema),
-reddish-brown urine,
- reddish-brown teeth, and ulcers which
destroy cartilage and bone,
3.causing the deformation of the nose,
ears, and fingers. Mental aberrations
such as hysteria, manic-depressive
psychosis, and delirium,
Hemoglobine derivates
unable to transport CO2
1. Methemoglobin: contains Fe 3 instead of Fe2
(e.g. nitrate/nitrite containing food or water)
2. Carboxyhemoglobin– CO poisoning, smokers
(cherry red colour)
3. Sulfhemoglobin – green