CGIER 37 - Haemoproteins III: Molecular diseases and mutant haemoglobins Flashcards
desferal functional group
hydroxylic acid
2 major functions of haemoglobin
transport of oxygen to tissues
transport of CO2 and protons away from tissues
carbamate
when CO2 combines with amino acid residue in globin chain of haemoglin it DOES NOT compete with O2
haemoglobin variants
HbA Adult a2β2
HbF Foetal a2γ2 (alpha2 gamma2)
HbA2 Minor adult form a2δ2 (alpha2 delta 2)
HbS Sickle-cell anaemia a2 βS2
where are alpha globin genes located on human chromosomes
chromosome 16
2 gene copies per chromosomes
where are beta globin genes on human chromosome
chromosome 11
1 gene copy per chromosome
what does P50 value measure
measures strength of binding to oxygen
the pO2 at which % saturation is 50%
Mb P50
1 Torr
Why is foetal haemoglobin different to adult haemoglobin
Gets O2 from mother and not environment directly
Must have a higher affinity for oxygen than adult as it must receive O2 from mother’s blood
HbA: P50
26.8 Torr in normal red blood cells
HbF P50
19 Torr
what causes mutant haemoglobins
change in DNA base sequence of one of the globin genes
change in amino acid sequence of globin
change in protein structure and function -> an inherited disease
classification of globin defects
HAEMOGLOBINOPATHIES
THALASSAEMIAS
HAEMOGLOBINOPATHIES
Normal amounts of defective globin subunits (qualitative defects)
THALASSAEMIAS
Abnormal amounts of normal globin subunits
quantitative defects
haemoglobinopathy - hameoglobin M
The proximal Histidine residue is replaced by Tyrosine in either the α or β subunit
In the presence of O2 and proximal tyrosine oxidation of the haem iron from the +II (ferrous) to the +III (ferric) state occurs
Result: As iron(III) cannot bind O2 transport of O2 is impaired.
Haemoglobinopathy - Haemoglobin S
An amino acid substitution occurs on the exterior of the β globin subunit
Glutamate CH2CH2COO- is replaced by Valine
- CH(CH3)2
In deoxyhaemoglobin S, Valine is exposed on the
surface of the molecule and creates a ‘sticky patch’
HbS molecules can aggregate to form insoluble fibres within the erythrocyte
The erythrocytes deform into ‘sickle cells’
Sickle cells get stuck in small capillary beds
Polar to hydrophobic interactions
superpolymer
precipitates out
short term consequences of haemoglobin S
Bone pain due to sickle cells stuck in capillary beds
long term consequences of haemoglobin S
Chronic anaemia due to destruction of erythrocytes Organ damage (kidneys, heart & lungs) Cerebrovascular accidents
diagnosis of haemoglobin. S
Protein or DNA analysis
Haemoglobin S treatment
Repeated blood transfusion
a thalassaemia
has too little a globin chains
β thalassaemia
has too little β globin chains
causes of thalassaemia
Thalassemia is a disorder caused by the weakening and destruction of red blood cells.
Thalassemia is caused by variant or missing genes that affect how the body makes hemoglobin
is thalassaemia quantitative or qualitative
quantitative
where is thalassaemia common in the world
Common in Mediterranean areas, parts of Africa and South East Asia
what does each Hb subunit contain
Each protein subunit contains a haem prosthetic group Fe(II)- protoporphyrin IX
