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Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2023-05-27 , DOI: 10.1038/s41392-023-01439-y
Xiumei Wu 1, 2 , Mengyun Xu 1 , Mengya Geng 1 , Shuo Chen 1 , Peter J Little 3, 4 , Suowen Xu 1 , Jianping Weng 1, 2, 5
Affiliation  

The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. The most common form of NCD is metabolic diseases, which affect people of all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding of the pathobiology of metabolic diseases will generate novel targets for improved therapies across the common metabolic spectrum. Protein posttranslational modification (PTM) is an important term that refers to biochemical modification of specific amino acid residues in target proteins, which immensely increases the functional diversity of the proteome. The range of PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, and several novel PTMs. Here, we offer a comprehensive review of PTMs and their roles in common metabolic diseases and pathological consequences, including diabetes, obesity, fatty liver diseases, hyperlipidemia, and atherosclerosis. Building upon this framework, we afford a through description of proteins and pathways involved in metabolic diseases by focusing on PTM-based protein modifications, showcase the pharmaceutical intervention of PTMs in preclinical studies and clinical trials, and offer future perspectives. Fundamental research defining the mechanisms whereby PTMs of proteins regulate metabolic diseases will open new avenues for therapeutic intervention.



中文翻译:


代谢疾病中的靶向蛋白质修饰:分子机制和靶向治疗



非传染性疾病(NCD)患病率不断上升,成为全球主要的公共卫生负担。非传染性疾病最常见的形式是代谢性疾病,它影响所有年龄段的人,通常通过危及生命的心血管并发症来表现其病理学。对代谢疾病病理学的全面了解将为改善常见代谢谱系的治疗产生新的靶点。蛋白质翻译后修饰(PTM)是一个重要术语,是指对目标蛋白质中特定氨基酸残基进行生化修饰,从而极大地增加蛋白质组的功能多样性。 PTM 的范围包括磷酸化、乙酰化、甲基化、泛素化、SUMO 化、neddylation、糖基化、棕榈酰化、肉豆蔻酰化、异戊二烯化、胆固醇化、谷胱甘肽化、S-亚硝基化、硫氢化、瓜氨酸化、ADP 核糖基化和几种新型 PTM。在此,我们对 PTM 及其在常见代谢疾病和病理后果中的作用进行了全面综述,包括糖尿病、肥胖、脂肪肝疾病、高脂血症和动脉粥样硬化。在此框架的基础上,我们通过关注基于 PTM 的蛋白质修饰,对代谢疾病中涉及的蛋白质和通路进行了全面的描述,展示了 PTM 在临床前研究和临床试验中的药物干预,并提供了未来的前景。定义蛋白质 PTM 调节代谢疾病机制的基础研究将为治疗干预开辟新途径。

更新日期:2023-05-28
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