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The Functional, Oxygen-linked Chloride Binding Sites Of Hemoglobin Are Contiguous Within A Channel In The Central Cavity

H. Ueno, J. Manning
Published 1992 · Chemistry, Medicine

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Chloride ion is a major allosteric regulator for many hemoglobins and particularly for bovine hemoglobin. A site-directed reagent for amino groups, methyl acetyl phosphate, when used forglobal rather thanselective modification of R (oxy) and T (deoxy) state bovine hemoglobin, can acetylate those functional amino groups involved in binding of chloride; the extensively acetylated hemoglobin tetramer retains nearly full cooperativity. The chloride-induced decrease in the oxygen affinity parallels the acetylation of bovine hemoglobin (i.e., their effects are mutually exclusive), suggesting that methyl acetyl phosphate is a good probe for the functional chloride binding sites in hemoglobins. Studies on theoverall alkaline Bohr effect indicates that the part of the contribution dependent on chloride and reduced by 60% after acetylation is due to amino groups, Val-1(α) and Lys-81(β); the remaining 40% is contributed by the imidazole side chain of His-146(β), which is not acetylated by methyl acetyl phosphate, and is not dependent on chloride. The five amino groups—Val-1(α), Lys-99(α), Met-1(β), Lys-81(β), and Lys-103(β)—of bovine hemoglobin that are acetylated in an oxygen-linked fashion are consideredfunctional chloride binding sites. Molecular modeling indicates that these functional chloride binding sites are contiguous from one end of the central cavity of hemoglobin to the other; some of them are aligned within a chloride channel connecting each end of the dyad axis. A generalization that can be made about hemoglobin function from these studies is that the blocking of positive charges within this channel either by binding of chloride or other anions, by covalent chemical modification such as acetylation, or by site-specific mutagenesis to create additional chloride binding sites each accomplish the same function of lowering the oxygen affinity of hemoglobin.
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