JBC, Vol. 250, Issue 12, 4786-4789, Jun, 1975
The alkylation of hemoglobin S by nitrogen mustard. High resolution proton nuclear magnetic resonance studies
L. W. Fung, C. Ho, E. F. Roth Jr and R. L. Nagel
Sickle cell hemoglobin (Hb S) treated with nitrogen mustard
(bis(beta-chloroethyl)methylamine hydrochloride) gives two reaction
products, one labile and one stable. After dialysis against buffer
solution, the remaining stable product is found to inhibit the
polymerization of deoxyhemoglobin S. High resolution proton nuclear
magnetic resonance has been used to study the structure and function of
this stable product and to investigate the nature of the binding sites of
nitrogen mustard to the hemoglobin molecule. The NMR results suggest that
the nitrogen mustard treatment of Hb S does not alter the heme environment
or the subunit interfaces of the hemoglobin molecule. Moreover, the NMR
spectra have also shown that the nitrogen mustard reacts with the beta2
histidines of the hemoglobin molecule and have suggested that several other
surface amino acid residues of the hemoglobin molecule are also affected by
the nitrogen mustard alkylation. These NMR findings are in good agreement
with the data obtained from biochemical studies of nitrogen mustard-treated
Hb S. The NMR spectra also indicate that nornitrogen mustard (which is also
effective in inhibiting sickling) binds with the hemoglobin molecule in a
manner identical with nitrogen mustard. Sulfur mustard, on the other hand,
produces no observable changes in the aromatic proton resonances, which is
consistent with the fact that it does not inhibit the polymerization of
deoxy-Hb S.
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