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Hemoglobin Genetics, Structure and Function

Learning Goals
1. Introduce the concept of gene families with an emphasis on the developmental regulation of globin genes.
2. Compare and contrast myoglobin and hemoglobin structure and function.
3. Appreciate the necessity of and structural basis for cooperativity of oxygen binding to hemoglobin
4. Explore the roles of H+, CO2 and 2,3-DPG as regulators of oxygen binding to hemoglobin.
5. Understand the Bohr effect.
6. Learn the molecular basis of sickle cell anemia and other hemoglobinopathies.

I. The Globin Genes
a. Structure and developmental regulation: alpha globin gene family, beta globin gene family
II. Overview of gas transport and pH regulation in humans
a. Transport O2 from a region of high concentration in the lungs to peripheral tissues where O2 pressure is
low. Metabolism creates CO2 and H+ that are transported back to the lungs.
III. Tertiary structures of myglobin and hemoglobin
a. Contain an Fe2+-protoporphyrin IX prosthetic group responsible for binding oxygen.
IV. Structure-function relationships in myoglobin and hemoglobin
a. Myoglobin  hyperbolic binding, hemoglobin  sigmoidal cooperative binding (complex subunit
structure)
b. Developmental forms of hemoglobin differ in subunit composition and binding affinity for O2.
c. Sequential cooperativity- binding of oxygen to one subunit induces a conformational change that is
partially transmitted to adjacent subunits. Trigger for change depends on orientation of Fe2+ within the
protoporphyrin ring.
d. Heterotropic negative allosteric regulators: H+ and CO2; decrease the affinity of hemoglobin for oxygen,
enhances the efficiency of oxygen unloading in the peripheral tissues.
e. Posititive homotropic allosteric effector: O2; enhances efficiency of H+ and CO2 unloading at the lungs
(reciprocal relationship between O2 and H+ = Bohr effect)
f. 2,3-diphosphoglycerate is a negative allosteric regulator of oxygen binding (binds to central cavity by
ionic interactions)
g. Teemperature affects O2 affinity of hemoglobin
V. Clinical consequences of mutations and altered expression of the globin genes
a. Sickle Cell Anemia
i. HbS: substitution of valine for glutamic acid at position six of the beta globin chain 
polymerization when deoxygenated, formation of intracellular fibers, sickle shape  reduced
defor
ii. Deformability of the red cell and defective passage through microcirculation
iii. Contact made by the valine of one molecule and a hydrophobic accepter pocket of the beta
subunit of another molecule (Glu prevents this interaction)
iv. Rate/extent of polymer formation depends on:
1. Degree of deoxygenation
2. Intracellular hemoglobin concentration
3. Relative amount of HbF present (inhibits polymerization)
v. Deformation of the RBC membrane leads to:
1. Dysregulation of red cell volume: Gardos effect (loss of K+, Cl- and H2O due to
increased intracellular Ca++)
2. Adhesion to the microvascular endothelium (clumping in vasculature)
vi. Current therapy = hydoxyurea  stimulates HbF production
vii. Electrophoresis to monitor hemoglobin constitution
viii. RFLP Analysis to diagnose sickle cell anemia
b. Thalassemias: Imbalance in the concentration of globin chains
i. Promoter mutations, frameshift mutations, splicing mutations
c. Hereditary persistence of fetal hemoglobin  imbalance in subunits
d. Hemoglobin C caused by point mutation Glu  Lys
e. Hemoglobin A1c = glycosylated hemoglobin (diabetic patients not taking insulin)