Hemoglobin Flashcards
What is the structure of hemoglobin?
Quaternary structure with 4 subunits: 2 alpha-chains and 2 beta-chains
Donut -> slight hole in the middle
Structure of hemoglobin vs myoglobin
Hemoglobin: tetramer, quaternary structure
Myoglobin: Monomer, only secondary structure?
Myoglobin and Hemoglobin bind oxygen in
Heme groups, which are protoporphyrin rings (4 pyrrole rings with N facing towards inside) with Fe in middle
Fe2+ has 2 additional coordination sites
Coordination sites of hemoglobin and myoglobin
Fe is slightly too big to fit well into the hole of protoporphyrin ring
5th coord site: proximal his
6th coord site: Fe
When oxygen binds to 6th coord site, radius decreases = Fe smaller -> fits into ring better!
Hemoglobin displays cooperative behaviour
Sigmoidal curve represents cooperativity in oxygen binding
- Oxygen is transported from the lungers where the partial pressure of oxygen is high (100torr) to the tissues where the pO2 is low (20torr)
What are the two states of hemoglobin?
T-state/T form = tense, deoxyhemoglobin
R-state/R form = relaxed, oxyhemoglobin
How does oxygen binding lead to transition from T state to R state?
- Binding of oxygen shifts the proximal histidine (pulls up Fe and proximal his)
- This results in movement of the corresponding alpha-helix
- This alters the interface of the alphabeta dimers
- These structural changes provide a path of communication between subunits, triggering a change from T to R, making it more favourable for oxygen to bind
Allosteric Regulator of Hemoglobin
2,3-BPG binds a pocket only found on T form (deoxy) and stabilizes it
- For the T to R transition to happen, 2,3-BPG must be expelled from the binding site
How is oxygen transferred from maternal hemoglobin to fetal hemoglobin?
- Fetal hemoglobin must bind oxygen when it is released from maternal hemoglobin
How is the affinity of fetal hemoglobin for oxygen increased?
Decreasing the affinity for 2,3-BPG will increase in oxygen binding
- Fetal hemoglobin is a tetramer with 2 alpha chains and 2 y chains
- The y chain is 72% identical to the beta chain- one change is His to Ser in 2,3-BPG binding pocket
Hydrogen ions and CO2 promote the release of oxygen
H+ and CO2 regulate oxygen binding to hemoglobin (Bohr effect)
CO2 from tissue diffuses and binds into hemoglobin -> CO2 + H2O < > H2CO3 < > HCO3- + H+
Proton produced lowers pH
How does pH influence oxygen binding?
- Low pH favours formation of a salt bridge that stabilizes (deoxy) form of hemoglobin, favouring release of oxygen
- At higher pH, His 146 is not protonated
CO2 promotes the release of oxygen
Cells most in need of oxygen use the end products of oxygen-dependent metabolism (CO2 and H+) to signal need for more oxygen
- CO2 reacts with terminal amino groups to form carbamate (neg charge)
- Carbamate groups form salt bridges at interface of alphabets dimers, stabilize deoxy and favour release of oxygen
Sick-Cell Anemia
- Caused by a mutation in both copies of the hemoglobin gene
- Sickle-cell hemoglobin (HbS) forms long fibers that deform the cell
- Sickle-cells rupture easily, leading to anemia
- HbS has Glu 6 -> Val 6 mutation on beta chains, which reduces the solubility of deoxy but not oxy form
- When there is high concentration of deoxy, Val 6 interacts with Phe 85 and Leu 88 to form aggregates
Sickle-Cell Hemoglobin
A = normal adult hemoglobin
S = sickle cell hemoglobin
Blue triangle = sticky path on deoxy
Pink triangle = sticky path on oxy and deoxy hemoglobin S
Deoxy S aggregation (all the shit sticks together)
