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

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

Published In Chem Biol Interact, (2011 Jun 30)

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 100ýýM 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 12.8-16.5kcal/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.

PubMed ID: 20934417 Exiting the NIEHS site

MeSH Terms: Catalytic Domain; Humans; Models, Molecular; Molecular Dynamics Simulation; Prostaglandins/metabolism*; Protein Binding; Pyruvaldehyde/metabolism*; Serum Albumin/metabolism*; Warfarin/metabolism*

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