B. By inhibiting the enzyme ribonucleotide reductase, hydroxyurea
has been shown to increase the levels of fetal Hb (HbF, a 2y2) by
mechanisms not fully understood. The increase in HbF concentra-
tions has the effect of decreasing HbS levels in the red blood cell. The
increased concentration of HbF disrupts the polymerization of HbS
and decreases the incidence of sickle cell crises. Hydroxyurea does
not affect either the oxygen affinity or cooperativity of oxygen bind-
ing of HbS, nor does it react with HbS to cause a posttranslational
modification or affect 2,3-BPG binding.
C. In adult hemoglobin 2,3-BPG binds to ionized residues in the
interface between the two P-chains, thus decreasing the oxygen affin-
ity. The y-chains of fetal hemoglobin have fewer ionized residues in
the corresponding interface and bind 2,3-BPG with less affinity,
which allows for a greater binding affinity for oxygen.
The quaternary structure of HbA allows it to bind oxygen with pos-
itive cooperativity giving a sigmoidal oxygen dissociation curve.
Sickle cell anemia results from the nonconservative substitution
of valine for glutamate at the sixth residue of the P-chain of
Precipitation of HbS is more likely to occur from exertion and deoxy-
genation. Treatment consists therefore of oxygen and hydration.
The stiff fibrous precipitate of HbS causes the red blood cell to
deform into the characteristic sickle shape and makes the nor-
mally malleable cell susceptible to hemolysis.
Schultz RM, Liebman MN. Proteins II: structure-function relationships in protein
families. In: Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations,
5th ed. New York: Wiley-Liss, 2002.
Weatherall DJ, et al. The hemoglobinopathies. In: Scriver CR, Beaudet AL, Sly W,
et al., eds. The Metabolic & Molecular Basis of Inherited Disease, 8th ed. New York:
McGraw-Hill, 2001.
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