New site(s) of methylglyoxal-modified human serum albumin, identified by multiple reaction monitoring, alter warfarin binding and prostaglandin metabolism

Michael J. Kimzey, Hussein N. Yassine, Brent M. Riepel, George Tsaprailis, Terrence J. Monks, Serrine S. Lau

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Methylglyoxal (MG) is a biologically reactive byproduct of glucose metabolism, levels of which increase in diabetes. MG modification of protein generates neutral hydroimidazolone adducts on arginine residues which can alter functional active sites. We investigated the site-specificity of MG adduction to human serum albumin (HSA) using multiple reaction monitoring (MRM) of 13 MG-modified tryptic peptides, each containing an internal arginine. Seven new sites for MG modification (R257 > R209 > R222 > R81 > R485 > R472 > R10) are described. Analysis of MG-treated HSA showed substantial R257 and R410 modification, with MG-modified R257 (at 100 μM MG) in drug site I causing significant inhibition of prostaglandin catalysis. The MG hydroimidazolone (MG-H1) adduct was modeled at R257, and molecular dynamics simulations and affinity docking revealed a decrease of 12.8-16.5 kcal/mol (S and R isomers, respectively) for warfarin binding in drug site I. Taken together, these results suggest that R257 is a likely site for MG modification in vivo, which may have functional consequences for prostaglandin metabolism and drug bioavailability.

Original languageEnglish (US)
Pages (from-to)122-128
Number of pages7
JournalChemico-Biological Interactions
Volume192
Issue number1-2
DOIs
StatePublished - Jun 30 2011

Keywords

  • 15-keto PGE
  • Arginine damage
  • Carbonyl stress
  • Diabetic complications
  • Dicarbonyl adduction
  • Human serum albumin
  • MG-H1
  • Methylgloxal
  • Multiple reaction monitoring
  • Prostaglandin
  • Warfarin

ASJC Scopus subject areas

  • Toxicology

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