Hemoglobin Flashcards
What is the primary function of Myoglobin(Mb)?
Store oxygen in muscle for release during periods of oxygen deprivation
Structural difference between Mb and Hb
Mb has one subunit protein with heme, Hb has 4
What is the primary function of Hemoglobin(Hb)?
Carry oxygen gas from lungs to tissues.
What is allosteric regulation?
Molecule binding to a region of the protein away from active site.
What are the three predominant residues in the interior of Mb?
Phe, Leu, Val
What are the four amino acid residues that are on the surface of Mb?
Asp, Glu, Lys, Arg
What is the role of the nonpolar residues in Mb?
They protect Fe2+ from oxidizing to Fe3+ as this ion would not bind to O2.
Which protein has affinity of O2 dependent on pH, CO2, and 2-3 BPG?
Hb–it has cooperative binding as well
What is cooperativity?
Events at one active site of a subunit can influence events at active sites of others.
What is a quaternary structure?
Association of two or more protein chains to form a functional unit.
MWC vs KNF model of cooperativity
MWC has changes in unison, KNF has changes occur sequentially
What state does Deoxy Hb exist in?
Tense state– has a reduced affinity for O2
What state does Oxy Hb exist in?
Relaxed state– has a higher affinity for O2
What proportion of subunits do 2-3 BPG, pH, and CO2 increase?
T state subunits
What would binding of each O2 molecule to Hb due to the equilibria?
It would shift towards the R state more
What is the role of Gly25?
Needed for close association of B/E helices
What is the role of His92?
Forms coordinate covalent bond with ferrous ion
What is the role of Asp94?
Creates salt link with imidazole His146
What is the role of Val98?
Carbonyl hydrogen bond with Tyr145/side-chain steric interactions with porphyrin ring
What is the role of Tyr145?
OH group forms H-bond with Val98 carbonyl(C=O)
What is the role of His146?
Carboxyl group forms a salt link with Lys40 from alpha chain
What does the curve of Mb look like
Hyperbolic
What does the curve of Hb look like
Sigmoidal
What is the affect of 2,3 BPG?
Binds to Hb and reduces its affinity for O2 by stabilizing the Tense state form.
What does Deoxy Hb carry and where?
CO2 and H+ from tissues into lungs
What does binding to oxygen release?
CO2 and H+ in the lungs
Lowering the pH would mean what in terms of affinity?
Lowering pH = more H+, decreases O2 affinity for Hb
Increasing the [CO2] would mean what in terms of affinity?
Decreases O2 affinity for Hb
What happens if [CO2] is increasing and pH is falling in the tissue?
Hb releases more O2(Bohr effect)
Why does lower pH affect the affinity?
Easier protonation of the His146 imidazole side chain, leading to an easier “R” to “T” transition
What happens when the His146-ASp94 interaction is compromised?
Loss of ionic interaction leading to a conformational change from T to R state in lungs-> Favors O2 binding. (Heme is pulled back into plane)
What is the E6V disease?
Sickle cell anemia. Point mutation occurs where Glu6 is replaced by Valine.
What is the affect of the valine mutation?
This creates a hydrophobic patch on dHb, causing aggregation, which leads to a distorted shape. The molecule shifts from R to T state and makes it more difficult to carry O2.
What is one drug design that is being used to combat sickle cell disease?
Voxelotor, which shifts the equilibrium of HbS to R state. It does this by decreasing the polymerization of HbS and blunting the effect of 2,3 BPG.
