Hemoglobin (Part 2)

Question 1

The four types of hemoglobin variants in adults:

Answer 1

1. HbA (a₂b₂; 90%)
2. HbF (a₂g₂; < 2%)
3. HbA₂ (a₂d₂; 2-5%)
4. HbA_1c (a₂b₂-glucose; 3-9%)

Question 2

HbF:

Answer 2

• fetal hemoglobin
• two alpha chains and two gamma chains.
• gamma chain helps pull oxygen away from the maternal blood (higher oxygen affinity than beta chains)

Question 3

Interestingly, Hb subunits in genes are arranged:

Answer 3

• in order of their expression during development
  
  1. embryo Hb subunits
  2. fetal Hb subunits
  3. adult Hb subunits

Question 4

Change in affinity of HbF relative to HbA is due to:

Answer 4

• a histidine to serine mutation in the BPG binding site.
• By shifting the equilibrium away from the T-form which binds BPG, HbF favors the R-form which binds oxygen more readily (higher affinity)

Question 5

Differences in affinity between HbF and HbA:

Answer 5

• HbF
  
  • lower affinity for BPG
  • higher affinity for oxygen
    • lower P₅₀
    • favors R-form of Hb

Question 6

HbA_1c is caused by:

Answer 6

• non-enzymatic chemical modification of HbA by glucose in the bloodstream
• glycation of the amino-terminus of Hb
  
  • removes positive charge, reduces affinity for BPG
  • higher oxygen affinity

Question 7

Persistent elevated levels of glucose in the blood will result in higher:

Answer 7

• HbA_1c levels
• diagnostic for diabetes

Question 8

Sickle Cell Anemia is due to:

Answer 8

• a single mutation of Glu-6 on the beta-chain to Val
• Val is hydrophobic
  • now their is a hydrophobic site on the surface of the protein. Hb starts to stick to one another, forming a chain, push on edge of RBC forming a crescent, cell eventually lyses.

Question 9

HbS has an additional hydrophobic patch (Val 6) which promotes polymerization in the _____ state only.

Answer 9

deoxy

Question 10

Thalassemias:

Answer 10

• Absence or decreased synthesis of functional alpha-globin or beta-globin chains.
• due to:
  
  • splicing defects
  • deletions of genes
  • altered regulatory elements

Question 11

The three classes of thalessemias:

Answer 11

• major (homozygous - 2 defective genes)
• minor (heterozygous - 1 defective gene)
• HFPH (hereditary persistence of fetal hemoglobin)

Question 12

Sickle Cell Anemia Treatments:

Answer 12

• Stimulate production of HbF
  
  • This replaces the beta chain with the gamma chain. The mutation is in the beta chain, so you just replace the beta chain with the gamma chain and have functional Hb.
• Bone marrow transplant
• Gene therapy