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Quantitative Analysis of Sex-Hormone-Binding Globulin Glycosylation in Liver Diseases by Liquid Chromatography–Mass Spectrometry Parallel Reaction Monitoring
Journal of Proteome Research ( IF 4.4 ) Pub Date : 2018-07-16 , DOI: 10.1021/acs.jproteome.8b00201
Wei Yuan , Julius Benicky , Renhuizi Wei , Radoslav Goldman , Miloslav Sanda

Sex-hormone-binding globulin (SHBG) is a liver-secreted glycoprotein and a major regulator of steroid distribution. It has been reported that the serum concentration of SHBG changes in liver disease. To explore the involvement of SHBG in liver disease of different etiologies in greater detail, we developed a sensitive and selective liquid chromatography–mass spectrometry parallel reaction monitoring workflow to achieve quantitative analysis of SHBG glycosylation microheterogeneity. The method uses energy-optimized “soft” fragmentation to extract informative Y ions for maximal coverage of glycoforms and their quantitative comparisons. A total of 15 N-glycoforms of two N-glycosites and 3 O-glycoforms of 1 O-glycosite of this low-abundance serum protein were simultaneously analyzed in the complex samples. At the same time, we were able to partially resolve linkage isoforms of the fucosylated glycoforms and to identify and quantify SHBG N-glycoforms that were not previously reported. The results show that both core and outer-arm fucosylation of the N-glycoforms increases with liver cirrhosis but that a further increase of fucosylation is not observed with hepatocellular carcinoma (HCC). In contrast, the α-2–6 sialylated glycoform of the O-glycopeptide of SHBG increases in liver cirrhosis, and a significant 2-fold further increase is observed in HCC. In general, we do not find a significant contribution of different liver disease etiologies to the observed changes in glycosylation; however, elevation of the newly reported HexNAc(4)Hex(6) N-glycoform is associated with alcoholic liver disease.

中文翻译:

液相色谱-质谱平行反应监测定量分析肝脏疾病中性激素结合球蛋白的糖基化

性激素结合球蛋白(SHBG)是肝脏分泌的糖蛋白,是类固醇分布的主要调节剂。据报道,肝脏疾病中SHBG的血清浓度发生变化。为了更详细地探讨SHBG在不同病因肝病中的参与,我们开发了一种灵敏且选择性的液相色谱-质谱并行反应监测工作流程,以实现SHBG糖基化微异质性的定量分析。该方法使用能量优化的“软”碎片来提取信息性的Y离子,以最大程度地覆盖糖型及其定量比较。在复杂样品中同时分析了该低丰度血清蛋白的总共15种N-糖基的N-糖基和3种O-糖基的1个O-糖基。同时,我们能够部分解决岩藻糖基化糖型的连接同工型,并鉴定和定量以前未报道的SHBG N-糖型。结果表明,N-糖型的核心和外部岩藻糖基化都随着肝硬化而增加,但是在肝细胞癌(HCC)中未观察到岩藻糖基化的进一步增加。相比之下,SHBG的O-糖肽的α-2–6唾液酸化糖型在肝硬化中会增加,而在HCC中会观察到显着的2倍进一步增加。总的来说,我们没有发现不同的肝病病因对糖基化的变化有明显的贡献。但是,新报道的HexNAc(4)Hex(6)N-糖型的升高与酒精性肝病有关。
更新日期:2018-07-18
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