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

Seetharama Acharya, A. ; Roy, Rajendra Prasad ; Dorai, Bhuvaneshwari (1991) 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 Journal of Protein Chemistry, 10 (3). pp. 345-358. ISSN 0277-8033

Full text not available from this repository.

Official URL: http://www.springerlink.com/content/m0q72w01622158...

Related URL: http://dx.doi.org/10.1007/BF01025633

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 forin 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(agr) 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 thepH, 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.

Item Type:Article
Source:Copyright of this article belongs to Springer.
Keywords:Post-translational Modification; Catalytic Power; Amadori Rearrangement
ID Code:52415
Deposited On:03 Aug 2011 14:03
Last Modified:03 Aug 2011 14:03

Repository Staff Only: item control page