Electrostatic modification at the amino termini of hemoglobin A

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

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Abstract

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
Volume269
Issue number4
StatePublished - Jan 28 1994

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Hemoglobin A
Static Electricity
Electrostatics
Stereochemistry
Ions
Derivatives
Salts
Acids
Aldehydes
Molecular modeling
Hydrogen
Functional groups
Oxygen
Hydrogen bonds
Molecules
galacturonic acid

ASJC Scopus subject areas

  • Biochemistry

Cite this

Acharya, A. S., Bobelis, D. J., & White, S. P. (1994). Electrostatic modification at the amino termini of hemoglobin A. Journal of Biological Chemistry, 269(4), 2796-2804.

Electrostatic modification at the amino termini of hemoglobin A. / Acharya, A. Seetharama; Bobelis, Daiva J.; White, Steven P.

In: Journal of Biological Chemistry, Vol. 269, No. 4, 28.01.1994, p. 2796-2804.

Research output: Contribution to journalArticle

Acharya, AS, Bobelis, DJ & White, SP 1994, 'Electrostatic modification at the amino termini of hemoglobin A', Journal of Biological Chemistry, vol. 269, no. 4, pp. 2796-2804.
Acharya AS, Bobelis DJ, White SP. Electrostatic modification at the amino termini of hemoglobin A. Journal of Biological Chemistry. 1994 Jan 28;269(4):2796-2804.
Acharya, A. Seetharama ; Bobelis, Daiva J. ; White, Steven P. / Electrostatic modification at the amino termini of hemoglobin A. In: Journal of Biological Chemistry. 1994 ; Vol. 269, No. 4. pp. 2796-2804.
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abstract = "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).",
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N2 - 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).

AB - 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).

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