Aldimine to ketoamine isomerization (Amadori rearrangement) potential at the individual nonenzymic glycation sites of hemoglobin a: Preferential inhibition of glycation by nucleophiles at sites of low isomerization potential

A. Seetharama Acharya, Rajendra Prasad Roy, Bhuvaneshwari Dorai

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Abstract

The relative roles of the two structural aspects of nonenzymic glycation sites of hemoglobin A, namely the ease with which the amino groups could form the aldimine adducts and the propensity of the microenvironments of the respective aldimines to facilitate the Amadori rearrangement, in dictating the site selectivity of nonenzymic glycation with aldotriose has been investigated. The chemical reactivity of the amino groups of hemoglobin A for in vitro reductive glycation with aldotriose is distinct from that in the nonreductive mode. The reactivity of amino groups of hemoglobin A toward reductive glycation (i.e., propensity for aldimine formation) decreases in the order Val-1(β), Val-1(α), Lys-66(β), Lys-61(α), and Lys-16(α). The overall reactivity of hemoglobin A toward nonreductive glycation decreased in the order Lys-16(α), Val-1(β), Lys-66(β), Lys-82(β), Lys-61(α), and Val-1(α). Since the aldimine is the common intermediate for both the reductive and nonreductive modification, the differential selectivity of protein for the two modes of glycation is clearly a reflection of the propensity of the microenvironments of nonenzymic glycation sites to facilitate the isomerization reaction (i.e., Amadori rearrangement). A semiquantitative estimate of this propensity of the microenvironment of the nonenzymic glycation sites has been obtained by comparing the nonreductive (nonenzymic) and reductive modification at individual glycation sites. The microenvironment of Lys-16(α) is very efficient in facilitating the rearrangement and the relative efficiency decreases in the order Lys-16(α), Lys-82(β), Lys-66(β), Lys-61(α), Val-1(β), and Val-1(α). The propensity of the microenvironment of Lys-16(α) to facilitate the Amadori rearrangement of the aldimine is about three orders of magnitude higher than that of Val-1(α) and is about 50 times higher than that of Val-1(β). The extent of nonenzymic glycation at the individual sites is modulated by various factors, such as the pH, concentration of aldotriose, and the concentration of the protein. The nucleophiles-such as tris, glycine ethyl ester, and amino guanidine-inhibit the glycation by trapping the aldotriose. The nonenzymic glycation inhibitory power of nucleophile is directly related to its propensity to form aldimine. Thus, the extent of inhibition of nonenzymic glycation at a given site by a nucleophile directly reflects the relative role of pKa of the site in dictating the glycation at that site. The nonenzymic glycation of an amino group of a protein is an additive/synergestic consequence of the propensity of the site to form aldimine adducts on one hand, and the propensity of its microenvironment to facilitate the isomerization of the aldimines to ketoamines on the other. The isomerization potential of microenvironment plays the dominant role in dictating the site specificity of the nonenzymic glycation of proteins.

Original languageEnglish (US)
Pages (from-to)345-358
Number of pages14
JournalJournal of Protein Chemistry
Volume10
Issue number3
DOIs
StatePublished - Jun 1991

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Hemoglobin A
Nucleophiles
Hemoglobin
Isomerization
Hemoglobins
Proteins
Chemical reactivity
Guanidine
Amino acids
Esters

Keywords

  • Amadori rearrangement
  • catalytic power
  • Post-translational modification

ASJC Scopus subject areas

  • Biochemistry

Cite this

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title = "Aldimine to ketoamine isomerization (Amadori rearrangement) potential at the individual nonenzymic glycation sites of hemoglobin a: Preferential inhibition of glycation by nucleophiles at sites of low isomerization potential",
abstract = "The relative roles of the two structural aspects of nonenzymic glycation sites of hemoglobin A, namely the ease with which the amino groups could form the aldimine adducts and the propensity of the microenvironments of the respective aldimines to facilitate the Amadori rearrangement, in dictating the site selectivity of nonenzymic glycation with aldotriose has been investigated. The chemical reactivity of the amino groups of hemoglobin A for in vitro reductive glycation with aldotriose is distinct from that in the nonreductive mode. The reactivity of amino groups of hemoglobin A toward reductive glycation (i.e., propensity for aldimine formation) decreases in the order Val-1(β), Val-1(α), Lys-66(β), Lys-61(α), and Lys-16(α). The overall reactivity of hemoglobin A toward nonreductive glycation decreased in the order Lys-16(α), Val-1(β), Lys-66(β), Lys-82(β), Lys-61(α), and Val-1(α). Since the aldimine is the common intermediate for both the reductive and nonreductive modification, the differential selectivity of protein for the two modes of glycation is clearly a reflection of the propensity of the microenvironments of nonenzymic glycation sites to facilitate the isomerization reaction (i.e., Amadori rearrangement). A semiquantitative estimate of this propensity of the microenvironment of the nonenzymic glycation sites has been obtained by comparing the nonreductive (nonenzymic) and reductive modification at individual glycation sites. The microenvironment of Lys-16(α) is very efficient in facilitating the rearrangement and the relative efficiency decreases in the order Lys-16(α), Lys-82(β), Lys-66(β), Lys-61(α), Val-1(β), and Val-1(α). The propensity of the microenvironment of Lys-16(α) to facilitate the Amadori rearrangement of the aldimine is about three orders of magnitude higher than that of Val-1(α) and is about 50 times higher than that of Val-1(β). The extent of nonenzymic glycation at the individual sites is modulated by various factors, such as the pH, concentration of aldotriose, and the concentration of the protein. The nucleophiles-such as tris, glycine ethyl ester, and amino guanidine-inhibit the glycation by trapping the aldotriose. The nonenzymic glycation inhibitory power of nucleophile is directly related to its propensity to form aldimine. Thus, the extent of inhibition of nonenzymic glycation at a given site by a nucleophile directly reflects the relative role of pKa of the site in dictating the glycation at that site. The nonenzymic glycation of an amino group of a protein is an additive/synergestic consequence of the propensity of the site to form aldimine adducts on one hand, and the propensity of its microenvironment to facilitate the isomerization of the aldimines to ketoamines on the other. The isomerization potential of microenvironment plays the dominant role in dictating the site specificity of the nonenzymic glycation of proteins.",
keywords = "Amadori rearrangement, catalytic power, Post-translational modification",
author = "Acharya, {A. Seetharama} and Roy, {Rajendra Prasad} and Bhuvaneshwari Dorai",
year = "1991",
month = "6",
doi = "10.1007/BF01025633",
language = "English (US)",
volume = "10",
pages = "345--358",
journal = "Protein Journal",
issn = "1572-3887",
publisher = "Springer New York",
number = "3",

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TY - JOUR

T1 - Aldimine to ketoamine isomerization (Amadori rearrangement) potential at the individual nonenzymic glycation sites of hemoglobin a

T2 - Preferential inhibition of glycation by nucleophiles at sites of low isomerization potential

AU - Acharya, A. Seetharama

AU - Roy, Rajendra Prasad

AU - Dorai, Bhuvaneshwari

PY - 1991/6

Y1 - 1991/6

N2 - The relative roles of the two structural aspects of nonenzymic glycation sites of hemoglobin A, namely the ease with which the amino groups could form the aldimine adducts and the propensity of the microenvironments of the respective aldimines to facilitate the Amadori rearrangement, in dictating the site selectivity of nonenzymic glycation with aldotriose has been investigated. The chemical reactivity of the amino groups of hemoglobin A for in vitro reductive glycation with aldotriose is distinct from that in the nonreductive mode. The reactivity of amino groups of hemoglobin A toward reductive glycation (i.e., propensity for aldimine formation) decreases in the order Val-1(β), Val-1(α), Lys-66(β), Lys-61(α), and Lys-16(α). The overall reactivity of hemoglobin A toward nonreductive glycation decreased in the order Lys-16(α), Val-1(β), Lys-66(β), Lys-82(β), Lys-61(α), and Val-1(α). Since the aldimine is the common intermediate for both the reductive and nonreductive modification, the differential selectivity of protein for the two modes of glycation is clearly a reflection of the propensity of the microenvironments of nonenzymic glycation sites to facilitate the isomerization reaction (i.e., Amadori rearrangement). A semiquantitative estimate of this propensity of the microenvironment of the nonenzymic glycation sites has been obtained by comparing the nonreductive (nonenzymic) and reductive modification at individual glycation sites. The microenvironment of Lys-16(α) is very efficient in facilitating the rearrangement and the relative efficiency decreases in the order Lys-16(α), Lys-82(β), Lys-66(β), Lys-61(α), Val-1(β), and Val-1(α). The propensity of the microenvironment of Lys-16(α) to facilitate the Amadori rearrangement of the aldimine is about three orders of magnitude higher than that of Val-1(α) and is about 50 times higher than that of Val-1(β). The extent of nonenzymic glycation at the individual sites is modulated by various factors, such as the pH, concentration of aldotriose, and the concentration of the protein. The nucleophiles-such as tris, glycine ethyl ester, and amino guanidine-inhibit the glycation by trapping the aldotriose. The nonenzymic glycation inhibitory power of nucleophile is directly related to its propensity to form aldimine. Thus, the extent of inhibition of nonenzymic glycation at a given site by a nucleophile directly reflects the relative role of pKa of the site in dictating the glycation at that site. The nonenzymic glycation of an amino group of a protein is an additive/synergestic consequence of the propensity of the site to form aldimine adducts on one hand, and the propensity of its microenvironment to facilitate the isomerization of the aldimines to ketoamines on the other. The isomerization potential of microenvironment plays the dominant role in dictating the site specificity of the nonenzymic glycation of proteins.

AB - The relative roles of the two structural aspects of nonenzymic glycation sites of hemoglobin A, namely the ease with which the amino groups could form the aldimine adducts and the propensity of the microenvironments of the respective aldimines to facilitate the Amadori rearrangement, in dictating the site selectivity of nonenzymic glycation with aldotriose has been investigated. The chemical reactivity of the amino groups of hemoglobin A for in vitro reductive glycation with aldotriose is distinct from that in the nonreductive mode. The reactivity of amino groups of hemoglobin A toward reductive glycation (i.e., propensity for aldimine formation) decreases in the order Val-1(β), Val-1(α), Lys-66(β), Lys-61(α), and Lys-16(α). The overall reactivity of hemoglobin A toward nonreductive glycation decreased in the order Lys-16(α), Val-1(β), Lys-66(β), Lys-82(β), Lys-61(α), and Val-1(α). Since the aldimine is the common intermediate for both the reductive and nonreductive modification, the differential selectivity of protein for the two modes of glycation is clearly a reflection of the propensity of the microenvironments of nonenzymic glycation sites to facilitate the isomerization reaction (i.e., Amadori rearrangement). A semiquantitative estimate of this propensity of the microenvironment of the nonenzymic glycation sites has been obtained by comparing the nonreductive (nonenzymic) and reductive modification at individual glycation sites. The microenvironment of Lys-16(α) is very efficient in facilitating the rearrangement and the relative efficiency decreases in the order Lys-16(α), Lys-82(β), Lys-66(β), Lys-61(α), Val-1(β), and Val-1(α). The propensity of the microenvironment of Lys-16(α) to facilitate the Amadori rearrangement of the aldimine is about three orders of magnitude higher than that of Val-1(α) and is about 50 times higher than that of Val-1(β). The extent of nonenzymic glycation at the individual sites is modulated by various factors, such as the pH, concentration of aldotriose, and the concentration of the protein. The nucleophiles-such as tris, glycine ethyl ester, and amino guanidine-inhibit the glycation by trapping the aldotriose. The nonenzymic glycation inhibitory power of nucleophile is directly related to its propensity to form aldimine. Thus, the extent of inhibition of nonenzymic glycation at a given site by a nucleophile directly reflects the relative role of pKa of the site in dictating the glycation at that site. The nonenzymic glycation of an amino group of a protein is an additive/synergestic consequence of the propensity of the site to form aldimine adducts on one hand, and the propensity of its microenvironment to facilitate the isomerization of the aldimines to ketoamines on the other. The isomerization potential of microenvironment plays the dominant role in dictating the site specificity of the nonenzymic glycation of proteins.

KW - Amadori rearrangement

KW - catalytic power

KW - Post-translational modification

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