Hemoglobin is the molecule responsible for oxygen transport by red blood cells.
Concentration within erythrocytes can approach 5 mM (most intracellular proteins never exceed 0.01 mM)
Structure and Function
Hemoglobin is made up of four subunits, almost entirely
a -helices – two chains (a and b ) that are practically identical
b
chain is very similar to myoglobin
early in gestation, fetal hemoglobin has a
z and an e chain; these are replaced fairly early by a and g , respectively
g
is replaced by b at birth – can be reactivated to treat certain diseases (hydroxyurea for sickle cell)
The oxygen carrying ability of hemoglobin is due to the heme group (porphyrine ring)
Fe(II) is chelated by nitrogen from a histidine residue; oxygen binds the iron from the other side
0.6 protons are released for each O2 hemoglobin binds, so low pH drives hemoglobin to release oxygen
Cooperativity
– first iron binds poorly, but increases affinity for next – hence sigmoidal binding curve (unlike myoglobin)
O2 binds all four subunits in the lungs; two O2 are offloaded in the tissues
two different models for hemoglobin cooperativity:
(1) Symmetry (concerted) Model
– postulates subunits can have two discrete levels of affinity, T (low) or R (high)
all four subunits will always have the same binding affinity
binding of O2 to one subunit will increase probability that all four will enter higher affinity state
(2) Sequential Model
– postulates that subunits can have range of binding affinity
binding of O2 to one subunit will increase the extent of the affinity of all four
2,3-bisphosphoglycerate (BPG)
– present in RBC’s at 3 mM (same concentration as hemoglobin)
necessary for sigmoidal binding – without it, hemoglobin acts like myoglobin, tightly binding O2
decreases
O2 affinity by binding a "hole" in hemoglobin that blocks O2 binding – holds subunits in low affinity state
altitude acclimitization: BPG concentration increases to compensate for lower O2 levels
lower affinity hemoglobin allows more oxygen to be delivered to tissues, even though less affinity in lungs
No carrier exists for CO2
– it is converted to HCO3- by carbonic anhydrase or made into carbamino compounds
Clinical Problems Associated with Hemoglobin
Since malaria uses red blood cells for replication, it is thought that hemoglobin problems increase resistance to malaria
endemic areas commonly have many hemoglobin disorders
Thalassemias
– imbalance in number of chains synthesized
a
thalassemia (Asia) – not enough a chains – stillborn
b
thalassemia (Mediterranean) – not enough b chains – can survive to adult due to persistance of fetal g chain, but rapidly become dependent on transfusion and die at 15-20 years due to iron poisoning from breakdown of transfused cells
Sickle Cell Disease
– glutamine to valine mutation(substitution) in b chain, allows hydrophobic interaction (pack into fibers)
normal gestation – does not appear until age 8
cells change shape, most often when deoxygenated
does not allow flow through capillaries – produces ischemia/severe pain