Flashcards in EXAM #1: HEMOGLOBIN Deck (54)
What is the most abundant form of Hb in adult? What subunits does it have?
- 2x alpha globins
- 2x beta globins
How many oxygen binding sites does Hb have?
4, one per subunit
What happens to oxygen binding as oxygen levels increase?
Hb binds O2 more efficiency at higher O2 concentrations b/c of cooperative binding
How does myoglobin's affinity for oxygen differ from Hb?
Myoglobin binds O2 with HIGH affinity at LOW oxygen concentrations
What is the effect of lower pH/ higher CO2/ lower O2 on oxygen binding?
Favors oxygen dissociation
What is the effect of higher pH/ lower CO2/ higher O2 on oxygen binding?
Favors oxygen binding
What is the effect of 2,3-BPG on oxygen binding?
What is Hb A2?
- 2 alpha globins
- 2 delta globins
What are the three Hb sub-types present in the early embryo? What are the subunits?
Hb Gower 1= 2-zeta and 2 epsilon
Hb Gower 2= 2 alpha and 2 epsilon
Hb Portland= 2 zeta and 2 gamma
What sub-type of Hb predominates as the embryo begins to age? What are the subunits?
Hb F= 2 alpha and 2 gamma
*****This is the major Hb of the fetus*****
When does an infant have a switch from predominantly Hb F to Hb A?
By 1 year old, the 98% of Hb is Hb A (vs. F in utero)
How does the oxygen affinity of Hb Gower 1,2, Portland, and F compare to Hb A?
V. high relative oxygen affinity
What is the purpose of increased oxygen affinity of the fetal and embryonic Hbs?
To "capture" oxygen diffusing from maternal circulation
What is the molecular basis of the higher affinity of Hb F for oxygen than Hb A?
- Histidine in B-chain
- Replaced with serine in gamma-chain
2,3-BPG binds to the Histidine in Hb A (Beta globin). Serine removes the positive charge that 2,3-BPG binds to, increasing the affinity of Hb F for oxygen.
What are the alpha-like globins? What chromosome are they encoded on?
*****Note that the pseudo genes are also encoded on chromosome 16--these cannot produce a functional protein product.*****
What are the beta-like globins? What chromosome are they encoded on?
What is the control region located upstream to the alpha-like globins?
Confers high level tissue specific expression of alpha-like globins
What is the control region located upstream of the beta-like globins?
Confers high level tissue specific expression of beta-like globins
What are hemoglobinopathies?
Disorders of hemoglobin
What are the two categories of hemoglobinopathies?
1) Structural variants-->Heinz bodies
What is the definition of Thalassemia?
Imbalanced synthesis of alpha and beta globins i.e. reduced synthesis of one or more of the globin chains
What is a Heinz body?
- Unstable Hb forms unstable complexes and is oxidized to methemoglobin
- Methemoglobin form hemichrome
- Hemichrome aggregates form Heinz bodies
What are the three major Hb structural variants?
1) Hb S
2) Hb C
3) Hb E
What is Hb S?
This is the Hb variant found in Sickle cell disease
How does Hb S differ from Hb A?
Glutamate at position 6 in the Beta-globin gene is replaced with VALINE
- Valine is v. hydrophobic and polymerizes when deoxygenated
What is the difference between Sickle Cell Trait and Sickle Cell Disease?
Trait= heterozygous mutation
Disease= homozygous mutation
Explain how the valine substitution at position 6 contributes to the pathology of Sickle Cell Disease.
- Valine is EXPOSED in deoxygenated Hb S
- Exposed valine forms a hydrophobic patch
- Hb S has a tendency to accumulate and stack
Stacked Hb forms the "Sickle" distortion of RBCs
What are the negative consequences of having Sickle-shaped RBCs?
- Clog the microcirculation
- Reduced lifespan
Leads to hemolytic anemia
What is the agent of choice for the management of sickle cell disease?