Electrostatic modification at the amino termini of hemoglobin A

A. Seetharama Acharya, Daiva J. Bobelis, Steven P. White

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The structural perturbations of the amino-terminal domains of hemoglobin A resulting from the carbamino adduct formation (a reversible in vivo electrostatic modification reaction) at Val-1(α) and Val-1(β) is expected to be mimicked in the derivatives of HbA reductively alkylated at its α- amino terminus with aldehydes containing a negatively charged functional group at their distal end (double-headed reagents). Derivatives of HbA with galacturonic acid linked through alkylamino linkage either to Val-1(α) or Val-1(β) (disubstituted derivatives) as well as to both Val-1(α) and Val- 1(β) (tetrasubsituted derivative) have been now prepared. All the three derivatives exhibit normal cooperativity but reduced O2 affinities. The functional consequence of the modification of HbA at its amino termini with D-galacuronic acid has been compared with that of the carboxymethylation of HbA at the same sites. This comparative study suggests that the stereochemistry of the carboxylate ion introduced into β-cleft of Hb dictates the level of reduction in the O2 affinity of the molecule seen on derivatization. However such a unique stereochemistry of the carboxylate ion of the reagent does not appear to be crucial to lower oxygen affinity when the modification is at the amino terminus of the α-chain. The molecular modeling studies demonstrate that the carboxylate ion of the carbamino adduct at the amino terminus of the β-chain as well as the carboxylate of carboxymethyl group at the same site are in a geometrical orientation that favors the formation of an intrachain ionic interaction with the ε-amino group of Lys-82(β). On the other hand the stereochemistry of a carboxylate ion of galacuronic acid on Val-1(β) appears to be appropriate to form either an intrachian salt bridge with ε-amino group of Ly2-82(β) of the same chain (intrachain) or alternatively an interchain salt bridge involving the ε- amino group of Lys-82(β) of the trans chain. We speculate that the latter, i.e. trans configuration is favored as a result of the potential of D- galacturonic acid bound to Val-1(β) to form an additional hydrogen bond with trans His-143(β).

Original languageEnglish (US)
Pages (from-to)2796-2804
Number of pages9
JournalJournal of Biological Chemistry
Issue number4
StatePublished - Jan 28 1994

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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