Week 2 - Hemoglobin and Myoglobin, Enzymes Flashcards
What is the effect of carbon monoxide on hemoglobin?
If 50% of the hemoglobin molecules have CO bound –> changes hemoglobin to a high affinity state: doesn’t release oxygen in tissues.
Describe what occurs in sickle-cell anaemia.
Glutamate, an acidic, negatively charged amino acids, makes interactions with water.
It is substituted by valine, a neutral non-polar hydrophobic amino acid, which does not interact with water. This causes beta subunits to cluster together and hemoglobin molecules stick to each other.
This creates aggregates of proteins and makes cell membranes more rigid.
Structure of heme
- Complex of protoporphyrin IX and ferrous iron (Fe2+)
- Iron held in centre of heme molecule bound to four nitrogens
- Heme Fe2+ can form two additional bonds: one on either side of the porphyrin ring
- One of these positions is coordinated to a histidine residue, and the other is available to bind oxygen
Interactions of subunits in hemoglobin:
- Tetramer
- Composed of two identical dimers (alpha beta)1 (alpha beta)2
- Within each dimer, polypeptide chains held tightly primarily by hydrophobic interactions
- 2 dimers held primarily by ionic bonds
- Weaker interactions between dimers allows them to move with respect to each other
Describe the two forms of hemoglobin.
“T” structure of hemoglobin: taut
- the two dimers interact through a network of hydrogen and ionic bonds: constrained movement of the polypeptide chains
- Low oxygen affinity form of hemoglobin
“R” form of hemoglobin: relaxed form
Binding of oxygen to hemoglobin causes rupture of some of the polar bonds between the alpha beta dimers, allowing movement.
-High affinity form of hemoglobin
-Oxygen binding promotes stabilization of the R state
Oxygen binding to haem in myoglobin:
- Fe in deoxymyoglobin is slightly below plane of ring
- Binding of oxygen causes movement of Fe into plane of ring
Describe the Bohr Effect.
- Release of oxygen from hemoglobin increases when pH decreases or pCO2 increases
- Hemoglobin has a decreased affinity for oxygen.
- Shift to right of oxygen dissociation curve
- Stabilization of T (deoxy) form
- ensures delivery of oxygen is coupled to demand
Mechanism of the Bohr Effect:
- Deoxy form of hemoglobin has a higher affinity for protons than oxyhemoglobin
- Ionizable groups: specific histidine side chains - higher pKa in deoxy - than oxyhemoglobin
Normal concentration of 2,3 BPG in red blood cells
Approximately 5 mM
Describe carbon monoxide poisoning.
- Blocks oxygen transport
- Combines with ferromyoglobin and ferrohaemoglobin
- CO binds to hemoglobin approximately 250x times more readily than oxygen
- Fatal when COHb > 50%
- CO binding increases affinity of oxygen for remaining subunits
Proportion of hemoglobin in adult hemoglobin:
- HbA: 90%
2. HbF:
Sickle cell anaemia
- Glutamate is mutated to valine in B-globin (HbS)
- Sticky hydrophobic pocket formed by valine allows deoxygenated HbS to polymerise
- Sickled cells more prone to lyse
- Sickle cells are more rigid: block microvasculature
- Point mutation
- Occurs in individuals with 2 mutant genes that code for synthesis of B chains
- At low oxygen tension, deoxyhemoglobin S polymerizes inside RBC: network of insoluble, fibrous polymers: stiffen and distort cell - rigid, misshapen RBC
- Such sickled cells frequently block blood flow in capillaries
Treatment:
- Analgesics
- Transfusion in patients at high risk for fatal occlusion of blood vessels
Thalassaemias
A group of genetic disorders where there is an imbalance between number of alpha and beta globin chains
Beta thalassaemias
Decreased or absent beta globin chain production;
Symptoms appear after birth;
Alpha chains are unable to form stable tetramers;
Alpha thalassaemias
- Decreased or absent alpha globin chain production
- Beta chains can form stable tetramers with increased affinity for oxygen
- Onset before birth
