Amadori rearrangement potential of hemoglobin at its glycation sites is dependent on the three-dimensional structure of protein

Parimala Nacharaju, A. Seetharama Acharya

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

The site selectivity of nonenzymic glycation of proteins has been suggested to be a consequence of the Amadori rearrangement activity of the protein at the respective glycation sites [Acharya, A. S., Roy, R. P., & Dorai, B. (1991) J. Protein Chem. 10, 345-358]. The catalytic activity that determines the potential of a site for nonenzymic glycation is the propensity of its microenvironment to isomerize the protein bound aldose (aldimine) to a protein bound ketose (ketoamine). The catalytic power of the microenvironment of the glycation sites could be endowed to them either by the amino acid sequence (nearest-neighbor linear effects) or by the higher order structure (tertiary/quaternary) of the protein (nearest-neighbor three-dimensional effect). In an attempt to resolve between these two structural concepts, the glycation potential of Val-1(α) and Lys-16(α), the residues of hemoglobin A exhibiting the least and the highest isomerization activity in the tetramer, respectively, has been compared in the segment α1-30, isolated α-chain, and the tetramer. When α-chain is used as the substrate for the nonenzymic glycation, the influence of the quaternary structure of the tetramer will be absent. Similarly, the contribution of the tertiary and quaternary structure of the protein will be absent when α1-30 is used as the substrate. The microenvironment of Lys-16(α) exhibited hardly any Amadori rearrangement activity in the segment α1-30. The tertiary structure of the α-chain induces a considerable degree of catalytic activity to the microenvironment of Lys-16(α) to isomerize the aldimine adduct at this site. The catalytic power of the microenvironment of Lys-16(α) is further enhanced by the quaternary structure of hemoglobin A. In contrast to the behavior of Lys-16(α), the catalytic activity of the microenvironment of Val-1(α) is reduced by the interaction of the quaternary structure of hemoglobin A almost by an order of magnitude. On the other hand, the loss of the tertiary structure of the α-chain reduced the catalytic activity of the microenvironment of Val-1(α) for nonenzymic glycation in a way similar to that seen with Lys-16(α). The perturbations of the local conformational features around Val-1(α) of hemoglobin A that occur on the removal of Arg-141(α) have very little influence on the catalytic activity at this microenvironment. The reactivity of Val-1(α) in horse hemoglobin for nonenzymic glycation is about five times higher than that of Val-1(α) of human hemoglobin. Val-1(α) is a part of the chloride binding site of hemoglobin A. The conformational elements of the chloride binding site of hemoglobin A are largely conserved in horse hemoglobin. The reactivity of Val-1(α) for nonenzymic glycation in des-Arg-141(α)-HbA and horse Hb establishes that the design principles of hemoglobin that contribute to the generation of a chloride binding site are distinct from the conformational features of the molecule that reduce the Amadori rearrangement activity of this site. The reactivity of Lys-16(α) in horse Hb and des-Arg-141(α)-hemoglobin A is nearly the same as that of human hemoglobin. The stereochemical features of this site are conserved well between the horse and human hemoglobin except for the replacement of Glu-116(α) by Asp in horse hemoglobin. The results thus establish that the Amadori rearrangement activity (catalytic power) of the glycation sites of hemoglobin A is a consequence of its three-dimensional structure rather than the amino acid sequence around the nonenzymic glycation site.

Original languageEnglish (US)
Pages (from-to)12673-12679
Number of pages7
JournalBiochemistry
Volume31
Issue number50
StatePublished - 1992

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Hemoglobin A
Hemoglobins
Horses
Catalyst activity
Quaternary Protein Structure
Proteins
Chlorides
Binding Sites
Tertiary Protein Structure
Amino Acid Sequence
Ketoses
Amino Acids
Glycosylated Hemoglobin A
Substrates
Viperidae
Isomerization
Molecules

ASJC Scopus subject areas

  • Biochemistry

Cite this

Amadori rearrangement potential of hemoglobin at its glycation sites is dependent on the three-dimensional structure of protein. / Nacharaju, Parimala; Acharya, A. Seetharama.

In: Biochemistry, Vol. 31, No. 50, 1992, p. 12673-12679.

Research output: Contribution to journalArticle

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AU - Acharya, A. Seetharama

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N2 - The site selectivity of nonenzymic glycation of proteins has been suggested to be a consequence of the Amadori rearrangement activity of the protein at the respective glycation sites [Acharya, A. S., Roy, R. P., & Dorai, B. (1991) J. Protein Chem. 10, 345-358]. The catalytic activity that determines the potential of a site for nonenzymic glycation is the propensity of its microenvironment to isomerize the protein bound aldose (aldimine) to a protein bound ketose (ketoamine). The catalytic power of the microenvironment of the glycation sites could be endowed to them either by the amino acid sequence (nearest-neighbor linear effects) or by the higher order structure (tertiary/quaternary) of the protein (nearest-neighbor three-dimensional effect). In an attempt to resolve between these two structural concepts, the glycation potential of Val-1(α) and Lys-16(α), the residues of hemoglobin A exhibiting the least and the highest isomerization activity in the tetramer, respectively, has been compared in the segment α1-30, isolated α-chain, and the tetramer. When α-chain is used as the substrate for the nonenzymic glycation, the influence of the quaternary structure of the tetramer will be absent. Similarly, the contribution of the tertiary and quaternary structure of the protein will be absent when α1-30 is used as the substrate. The microenvironment of Lys-16(α) exhibited hardly any Amadori rearrangement activity in the segment α1-30. The tertiary structure of the α-chain induces a considerable degree of catalytic activity to the microenvironment of Lys-16(α) to isomerize the aldimine adduct at this site. The catalytic power of the microenvironment of Lys-16(α) is further enhanced by the quaternary structure of hemoglobin A. In contrast to the behavior of Lys-16(α), the catalytic activity of the microenvironment of Val-1(α) is reduced by the interaction of the quaternary structure of hemoglobin A almost by an order of magnitude. On the other hand, the loss of the tertiary structure of the α-chain reduced the catalytic activity of the microenvironment of Val-1(α) for nonenzymic glycation in a way similar to that seen with Lys-16(α). The perturbations of the local conformational features around Val-1(α) of hemoglobin A that occur on the removal of Arg-141(α) have very little influence on the catalytic activity at this microenvironment. The reactivity of Val-1(α) in horse hemoglobin for nonenzymic glycation is about five times higher than that of Val-1(α) of human hemoglobin. Val-1(α) is a part of the chloride binding site of hemoglobin A. The conformational elements of the chloride binding site of hemoglobin A are largely conserved in horse hemoglobin. The reactivity of Val-1(α) for nonenzymic glycation in des-Arg-141(α)-HbA and horse Hb establishes that the design principles of hemoglobin that contribute to the generation of a chloride binding site are distinct from the conformational features of the molecule that reduce the Amadori rearrangement activity of this site. The reactivity of Lys-16(α) in horse Hb and des-Arg-141(α)-hemoglobin A is nearly the same as that of human hemoglobin. The stereochemical features of this site are conserved well between the horse and human hemoglobin except for the replacement of Glu-116(α) by Asp in horse hemoglobin. The results thus establish that the Amadori rearrangement activity (catalytic power) of the glycation sites of hemoglobin A is a consequence of its three-dimensional structure rather than the amino acid sequence around the nonenzymic glycation site.

AB - The site selectivity of nonenzymic glycation of proteins has been suggested to be a consequence of the Amadori rearrangement activity of the protein at the respective glycation sites [Acharya, A. S., Roy, R. P., & Dorai, B. (1991) J. Protein Chem. 10, 345-358]. The catalytic activity that determines the potential of a site for nonenzymic glycation is the propensity of its microenvironment to isomerize the protein bound aldose (aldimine) to a protein bound ketose (ketoamine). The catalytic power of the microenvironment of the glycation sites could be endowed to them either by the amino acid sequence (nearest-neighbor linear effects) or by the higher order structure (tertiary/quaternary) of the protein (nearest-neighbor three-dimensional effect). In an attempt to resolve between these two structural concepts, the glycation potential of Val-1(α) and Lys-16(α), the residues of hemoglobin A exhibiting the least and the highest isomerization activity in the tetramer, respectively, has been compared in the segment α1-30, isolated α-chain, and the tetramer. When α-chain is used as the substrate for the nonenzymic glycation, the influence of the quaternary structure of the tetramer will be absent. Similarly, the contribution of the tertiary and quaternary structure of the protein will be absent when α1-30 is used as the substrate. The microenvironment of Lys-16(α) exhibited hardly any Amadori rearrangement activity in the segment α1-30. The tertiary structure of the α-chain induces a considerable degree of catalytic activity to the microenvironment of Lys-16(α) to isomerize the aldimine adduct at this site. The catalytic power of the microenvironment of Lys-16(α) is further enhanced by the quaternary structure of hemoglobin A. In contrast to the behavior of Lys-16(α), the catalytic activity of the microenvironment of Val-1(α) is reduced by the interaction of the quaternary structure of hemoglobin A almost by an order of magnitude. On the other hand, the loss of the tertiary structure of the α-chain reduced the catalytic activity of the microenvironment of Val-1(α) for nonenzymic glycation in a way similar to that seen with Lys-16(α). The perturbations of the local conformational features around Val-1(α) of hemoglobin A that occur on the removal of Arg-141(α) have very little influence on the catalytic activity at this microenvironment. The reactivity of Val-1(α) in horse hemoglobin for nonenzymic glycation is about five times higher than that of Val-1(α) of human hemoglobin. Val-1(α) is a part of the chloride binding site of hemoglobin A. The conformational elements of the chloride binding site of hemoglobin A are largely conserved in horse hemoglobin. The reactivity of Val-1(α) for nonenzymic glycation in des-Arg-141(α)-HbA and horse Hb establishes that the design principles of hemoglobin that contribute to the generation of a chloride binding site are distinct from the conformational features of the molecule that reduce the Amadori rearrangement activity of this site. The reactivity of Lys-16(α) in horse Hb and des-Arg-141(α)-hemoglobin A is nearly the same as that of human hemoglobin. The stereochemical features of this site are conserved well between the horse and human hemoglobin except for the replacement of Glu-116(α) by Asp in horse hemoglobin. The results thus establish that the Amadori rearrangement activity (catalytic power) of the glycation sites of hemoglobin A is a consequence of its three-dimensional structure rather than the amino acid sequence around the nonenzymic glycation site.

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