SICKLE-CELL-ANEMIA_37541 - SICKLE CELL ANEMIA Historical...

SICKLE CELL ANEMIA
Historical Summary
• 1904 Abnormal “pear shaped elongate forms” of red cells
first observed by a medical intern on a blood smear from a
West Indian dental student. Findings published in 1910.
• 1922 Similar observations; falciform (sickle) shape of red
cells noted, leading to name of disease.
• 1927 Sickling associated with deoxygenation of red cells.
Cells that were irreversibly sickled even in presence of
oxygen were later proposed to have a membrane defect.
• 1949 Electrophoresis of hemoglobin (HbS) from sickle cell
anemia patient demonstrated it migrated differently from
normal hemoglobin (HbA). Latent form (sickle cell trait)
showed both HbS and HbA.
• First instance that a genetic disorder traced directly to an
abnormal protein

SICKLE CELL ANEMIA
Historical Summary (cont’d)
1950 Ingram showed that HbA and HbS differ by a single
amino acid. He did this by degrading Hb with trypsin and
separated resulting peptides by 2 dimensional paper
chromatography (“fingerprinting”).
Comparing peptide patterns from HbA and HbS, a single
peptide differed in position.The change subsequently
shown to be a replacement of an acidic (Glu) with a
hydrophobic amino acid (Val) at position 6 of the beta
chain.
1975 X-ray crystallographic structure of HbS solved.
Provided evidence that when deoxygenated, HbS is much
less soluble than corresponding HbA. Abnormal tetramers
polymerize to form linear filaments which then associate
into larger fibers.Their accumulation deforms red cells,
damages their membranes and renders them stiff and
inflexible.

REVIEW OF HEMOGLOBIN
PROPERTIES

CHARACTERISTICS OF GLOBIN
PROTEINS
· Single polypeptide chain of ~150 amino acids
· High proportion of α -helix: 75% of the amino acids are
associated with 8 α -helices
· α -helices are organized into a tightly packed, nearly
spherical, globular tertiary structure
· Highly soluble: polar amino acids on the exterior surface
of the protein
· Each globin contains one noncovalently bound heme
group

Hemoglobin
· Synthesized in RBC precursor
cells: reticulocytes and
erythroblasts
· Synthesis is tightly controlled
and dictated by the
concentration of heme
• Tetramer of 2 α -globin and 2 β -
globin chains
• Best described as a dimer of the
heterodimer ( αβ )

INTERACTIONS WITH O
2
* Can bind up to 4 O
2
molecules
* Binding of O
2
is
cooperative: the binding
of 1 O
2
influences the
binding of another.

DEOXYGENATED VS. OXYGENATED HEMOGLOBIN
• As deoxygenated hemoglobin becomes oxygenated, significant structural
changes take place
•
the proximal histidine and its helix shift
•
one heterodimer rotates and slides relative to the other
•
existing noncovalent bonds are broken and replaced by new
ones
• Approximately 30 amino acids participate in the noncovalent (hydrogen
and/or electrostatic) interactions between the 2 heterodimers
· Interactions between the two heterodimers are stronger in the T (tense)-
state = deoxygenated hemoglobin
· These interactions are weaker in the R (relaxed)-state = oxygenated
hemoglobin
· The R-state has a higher affinity for O
2
than the T-state

DEOXYGENATED VS. OXYGENATED