Alexander K. Hurben, Qi Zhang, James J. Galligan, Natalia Tretyakova* and Luke Erber*,
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引用次数: 0
摘要
甲基乙二醛(MGO)是一种亲电的α-氧代甲醛,内源产生于碳水化合物的新陈代谢,外源产生于糖类的自氧化、脂类的降解以及食品和饮料加工过程中的发酵。MGO 可与蛋白质和 DNA 中的亲核部位发生反应,形成共价加合物。人们认为,MGO 诱导的高级糖化终产物(如蛋白质和 DNA 加合物)与氧化应激、炎症、糖尿病、癌症、肾功能衰竭和神经退行性疾病有关。此外,人们还假设 MGO 会形成有毒的 DNA 蛋白交联(DPC),但参与细胞中这种交联的蛋白质的身份尚未确定。在本研究中,我们使用基于质谱的蛋白质组学方法量化了暴露于 MGO 的人体细胞中 DPC 的形成,并鉴定了暴露于 MGO 时 DNA 上的滞留蛋白质。共发现 265 种蛋白质参与了 MGO 衍生的 DPC 形成,包括参与端粒组织、核小体组装和基因表达的基因产物。体外实验证实了 DNA 与甘油醛-3-磷酸脱氢酶(GAPDH)以及组蛋白 H3.1 和 H4 之间的 DPC 形成。总之,我们的研究首次证明了 MGO 在活细胞中介导的 DNA 蛋白交联,这促使我们今后研究这些毒性病变与癌症、糖尿病和其他与 MGO 水平升高有关的疾病的相关性。
Endogenous Cellular Metabolite Methylglyoxal Induces DNA–Protein Cross-Links in Living Cells
Methylglyoxal (MGO) is an electrophilic α-oxoaldehyde generated endogenously through metabolism of carbohydrates and exogenously due to autoxidation of sugars, degradation of lipids, and fermentation during food and drink processing. MGO can react with nucleophilic sites within proteins and DNA to form covalent adducts. MGO-induced advanced glycation end-products such as protein and DNA adducts are thought to be involved in oxidative stress, inflammation, diabetes, cancer, renal failure, and neurodegenerative diseases. Additionally, MGO has been hypothesized to form toxic DNA–protein cross-links (DPC), but the identities of proteins participating in such cross-linking in cells have not been determined. In the present work, we quantified DPC formation in human cells exposed to MGO and identified proteins trapped on DNA upon MGO exposure using mass spectrometry-based proteomics. A total of 265 proteins were found to participate in MGO-derived DPC formation including gene products engaged in telomere organization, nucleosome assembly, and gene expression. In vitro experiments confirmed DPC formation between DNA and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), as well as histone proteins H3.1 and H4. Collectively, our study provides the first evidence for MGO-mediated DNA–protein cross-linking in living cells, prompting future studies regarding the relevance of these toxic lesions in cancer, diabetes, and other diseases linked to elevated MGO levels.
期刊介绍:
ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology.
The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies.
We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.