کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2568241 1128430 2015 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Site specific modification of the human plasma proteome by methylglyoxal
ترجمه فارسی عنوان
تغییر محل خاص پروتئین پلاسمای انسانی توسط متیل گلیکسال
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
چکیده انگلیسی


• Methylglyoxal (MG) selectively modifies arginine sites in human plasma proteome.
• Dihydroxyimidazolidine and hydroimidazolone adducts on serum albumin identified
• MG modification on albumin R257 associated with loss of drug site I binding capacity
• MRM-tandem mass spectrometry enables sensitive detection of albumin MG-R257.
• Site-specific MG modification may represent a useful monitor of effective therapy of T2DM.

Increasing evidence identifies dicarbonyl stress from reactive glucose metabolites, such as methylglyoxal (MG), as a major pathogenic link between hyperglycemia and complications of diabetes. MG covalently modifies arginine residues, yet the site specificity of this modification has not been thoroughly investigated. Sites of MG adduction in the plasma proteome were identified using LC–MS/MS analysis in vitro following incubation of plasma proteins with MG. Treatment of plasma proteins with MG yielded 14 putative MG hotspots from five plasma proteins (albumin [nine hotspots], serotransferrin, haptoglobin [2 hotspots], hemopexin, and Ig lambda-2 chain C regions). The search results revealed two versions of MG-arginine modification, dihydroxyimidazolidine (R + 72) and hydroimidazolone (R + 54) adducts. One of the sites identified was R257 in human serum albumin, which is a critical residue located in drug binding site I. This site was validated as a target for MG modification by a fluorescent probe displacement assay, which revealed significant drug dissociation at 300 μM MG from a prodan–HSA complex (75 μM). Moreover, twelve human plasma samples (six male, six female, with two type 2 diabetic subjects from both genders) were analyzed using multiple reaction monitoring (MRM) tandem mass spectrometry and revealed the presence of the MG-modified albumin R257 peptide. These data provide insights into the nature of the site-specificity of MG modification of arginine, which may be useful for therapeutic treatments that aim to prevent MG-mediated adverse responses in patients.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 289, Issue 2, 1 December 2015, Pages 155–162
نویسندگان
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