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我院一论文在Antioxidants & Redox Signaling上在线发表
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我院牛卫宁副教授和美国密歇根大学以及内布拉斯加大学的研究者合作研究发现,在细胞氧化应激条件下胱硫醚-β-合成酶(CBS)能被谷胱甘肽化修饰,从而使CBS活性提高2~3倍,CBS活性的改变能影响细胞内气体信号分子H2S、半胱氨酸以及谷胱甘肽的合成。近日,该研究论文被自由基领域的权威期刊Antioxidants & Redox Signaling在线发表。牛卫宁副教授为该论文的第一作者,第一署名单位为西北工业大学生命学院空间生物实验模拟技术重点实验室。

在细胞转硫化途径中CBS催化同型半胱氨酸合成半胱氨酸,而半胱氨酸是体内谷胱甘肽合成的前体物质,其突变引起高同型半胱氨酸血症。同时CBS也是体内合成气体信号分子H2S的三种酶之一,H2S合成的改变与体内多种疾病相关。以前研究发现HepG2细胞在氧化应激条件下CBS蛋白表达量并未发生改变,但细胞CBS活性提高,具体的分子机制并不清楚。在该论文中我们发现在氧化压力下CBS的Cys346残基能被谷胱甘肽特异性修饰,谷胱甘肽化CBS活性提高2~3倍。我们的研究结果表明谷胱甘肽化是一种新的CBS翻译后修饰机制,在氧化压力下CBS的谷胱甘肽化能调控其活性,从而潜在影响细胞内半胱氨酸、谷胱甘肽以及H2S的合成。

本研究工作得到国家自然科学基金(20802057)和西北工业大学基础研究基金(JC201161)资助。

Abstract

Aims. Cystathionine β-synthase (CBS) catalyzes the first and rate-limiting step in the two-step transsulfuration pathway that converts homocysteine to cysteine. It is also one of three major enzymes responsible for the biogenesis of H2S, a signaling molecule. We have previously demonstrated that CBS is activated in cells challenged by oxidative stress, but the underlying molecular mechanism of this regulation has remained unclear.Results. Herein, we demonstrate that S-glutathionylation of CBS enhances its activity ~2-fold in vitro. Loss of this postranslational modification in the presence of dithiothreitol results in reversal to basal activity. Cys346 was identified as the site for S-glutathionylation by a combination of mass spectrometric, mutagenesis and activity analyses. To test the physiological relevance of S-glutathionylation-dependent regulation of CBS, HEK293 cells were oxidatively challenged with peroxide, which is known to enhance the transsulfuration flux. Under these conditions, CBS glutathionylation levels increased and was correlated with an ~3-fold increase in CBS activity. Innovation. Collectively, our results reveal a novel posttranslational modification of CBS, i.e. glutathionylation, which functions as an allosteric activator under oxidative stress conditions permitting enhanced synthesis of both cysteine and H2S.Conclusions. Our study elucidates a molecular mechanism for increased cysteine and therefore glutathione, synthesis via glutathionylation of CBS. They also demonstrate the potential for increased H2S production under oxidative stress conditions particularly in tissues where CBS is a major source of H2S.

论文链接:http://www.ncbi.nlm.nih.gov/pubmed/24893130

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