Molecular basis for the anti-sickling activity of aromatic amino acids and related compounds: a proton nuclear magnetic resonance investigation.
High-resolution proton nuclear magnetic resonance spectroscopy and relaxation techniques have been used to investigate the interactions of sickle cell hemoglobin (Hb S) and human normal adult hemoglobin (Hb A) with p-bromobenzyl alcohol, L-phenylalanine, L-tryptophan, and L-valine. With the exception of valine, all these compounds inhibit the polymerization of deoxy-Hb S [Noguchi, C. T., & Schechter, A. N. (1978) Biochemistry 17, 5455)). Using transferred nuclear Overhauser effects among the proton resonances of the compound of interest and the corresponding longitudinal relaxation rates (T1(-1], we have shown that the binding of each of the compounds investigated to deoxy-Hb S is comparable to that to deoxy-Hb A. Intermolecular transferred nuclear Overhauser effects have been observed between proton resonances of the anti-sickling compounds and specific protons situated in the heme pockets of Hb. On the basis of these results, we suggest that one binding site, common to all compounds with anti-sickling activity, is at or near the heme pockets in the alpha and beta chains of both deoxy-HB S and deoxy-Hb A. The proton T1(-1) values of the histidyl residues situated over the surface of the hemoglobin molecule indicate that a second binding site is located at or near the beta 6 position, containing the mutation in Hb S (beta 6Glu----Val). The binding of the compounds investigated to the latter site induces conformational changes in the amino-terminal domains of the beta chains.(ABSTRACT TRUNCATED AT 250 WORDS)
D000986:Antisickling Agents; D001592:Benzyl Alcohols / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000494:pharmacology*; D006441:Hemoglobin A / Q000378:metabolism*; D006451:Hemoglobin, Sickle / Q000378:metabolism*; D006801:Humans; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D010649:Phenylalanine / Q000494:pharmacology*; D011487:Protein Conformation; D014364:Tryptophan / Q000494:pharmacology*; D014633:Valine / Q000494:pharmacology*
D000986:Antisickling Agents; D001592:Benzyl Alcohols; D001593:Benzyl Compounds; D006451:Hemoglobin, Sickle; D046911:Macromolecular Substances; D010649:Phenylalanine; C048038:4-bromobenzyl alcohol; D014364:Tryptophan; D006441:Hemoglobin A; D014633:Valine