Glycation of human β2-microglobulin in patients with hemodialysis-associated amyloidosis: identification of the glycated sites

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Abstract

β-Microglobulin (β2M) is a major component forming amyloid deposits in patients with hemodialysis-associated amyloidosis (HAA), a serious complication of long-term hemodialysis. Recently, we demonstrated that β2M modified with the Maillard reaction is a definite constituent of amyloid deposits in patients with HAA. Our further study demonstrated that this modified β2M induces not only chemotaxis of monocytes but also secretion of tumor necrosis factor-α, interleukin-1β, and interleukin-6 from macrophages, suggesting the potential link of glycation of β2M by the Maillard reaction to the pathogenesis of HAA. The present study was undertaken to identify the glycated site(s) of β2M purified from long-term hemodialysis patients as well as β2M incubated with glucose in vitro. Borotritide-treated β2M was cleaved by endoproteinase Lys-C, and peptides were isolated by reverse-phase high-performance liquid chromatography, followed by amino acid sequence analysis and fast atom bombardment mass spectrometry to identify the glycated site. The glycated sites of β2M formed in vivo were found to be almost the same as those of glycated β2M in vitro. The primary glycated site was the α-amino group of the amino terminal isoleucine. Other minor sites were the ∈-amino groups of Lys-19, -41, -48, -58, -91, and -94. Computer graphics of the three-dimensional structure of β2M suggested that the high specificity for the glycated site at Ile-1 may be explained by its high solvent accessibility and the nearby imida/ole group of His-31 as an acid-base catalyst of the Amadori rearrangement.

Original languageEnglish
Pages (from-to)12149-12159
Number of pages11
JournalBiochemistry
Volume33
Issue number40
Publication statusPublished - 1994 Dec 1
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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