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Implication of homocysteine in protein quality control processes.
Biochimie ( IF 3.9 ) Pub Date : 2019-06-30 , DOI: 10.1016/j.biochi.2019.06.017 V Sudhakar Reddy 1 , Jamma Trinath 2 , G Bhanuprakash Reddy 1
Biochimie ( IF 3.9 ) Pub Date : 2019-06-30 , DOI: 10.1016/j.biochi.2019.06.017 V Sudhakar Reddy 1 , Jamma Trinath 2 , G Bhanuprakash Reddy 1
Affiliation
Homocysteine (Hcy) is a key metabolite generated during methionine metabolism. The elevated levels of Hcy in the blood are reffered to as hyperhomocystenimeia (HHcy). The HHcy is caused by impaired metabolism/deficiency of either folate or B12 or defects in Hcy metabolism. Accumulating evidence suggests that HHcy is associated with cardiovascular and brain diseases including atherosclerosis, endothelial injury, and stroke etc. Vitamin B12 (cobalamin; B12) is a water-soluble vitamin essential for two metabolic reactions. It acts as a co-factor for methionine synthase and L-methylmalonyl-CoA mutase. Besides, it is also vital for DNA synthesis and maturation of RBC. Deficiency of B12 is associated with haematological and neurological disorders. Hyperhomocysteinemia (HHcy)-induced toxicity is thought to be mediated by the accumulation of Hcy and its metabolites, homocysteinylated proteins. Cellular protein quality control (PQC) is essential for the maintenance of proteome integrity, and cell viability and its failure contributes to the development of multiple diseases. Chaperones, unfolded protein response (UPR), ubiquitin-proteasome system (UPS), and autophagy are analogous strategies of PQC that maintain cellular proteome integrity. Recently, multiple studies reported that HHcy responsible for perturbation of PQC by reducing chaperone levels, activating UPR, and impairing autophagy. Besides, HHcy also induce cytotoxicity, inflammation, protein aggregation and apoptosis. It has been shown that some of the factors including altered SIRT1-HSF1 axis and irreversible homocysteinylation of proteins are responsible for folate and/or B12 deficiency or HHcy-induced impairment of PQC. Therefore, this review highlights the current understanding of HHcy in the context of cellular PQC and their pathophysiological and clinical consequences, epigenomic changes, therapeutic implications of B12, and chemical chaperones based on cell culture and experimental animal models.
中文翻译:
同型半胱氨酸在蛋白质质量控制过程中的意义。
同型半胱氨酸(Hcy)是蛋氨酸代谢过程中产生的关键代谢产物。血液中Hcy的升高水平被称为高同型半胱氨酸血症(HHcy)。HHcy是由叶酸或B12的新陈代谢不足/缺乏或Hcy代谢缺陷引起的。越来越多的证据表明,HHcy与心血管疾病和脑疾病有关,包括动脉粥样硬化,内皮损伤和中风等。维生素B12(钴胺素; B12)是两种代谢反应必不可少的水溶性维生素。它充当蛋氨酸合酶和L-甲基丙二酰-CoA突变酶的辅助因子。此外,它对于红细胞的DNA合成和成熟也至关重要。B12缺乏与血液和神经系统疾病有关。高同型半胱氨酸血症(HHcy)诱导的毒性被认为是由Hcy及其代谢产物(同型半胱氨酸化蛋白)的积累介导的。细胞蛋白质质量控制(PQC)对于维持蛋白质组完整性是必不可少的,而细胞生存力及其衰竭会导致多种疾病的发展。伴侣蛋白,未折叠蛋白应答(UPR),泛素-蛋白酶体系统(UPS)和自噬是PQC的类似策略,可维持细胞蛋白质组的完整性。最近,多项研究报道,HHcy通过降低分子伴侣水平,激活UPR和损害自噬来引起PQC的紊乱。此外,HHcy还诱导细胞毒性,炎症,蛋白质聚集和凋亡。已经显示出某些因素,包括SIRT1-HSF1轴的改变和蛋白质的不可逆同型半胱氨酸化,是造成叶酸和/或B12缺乏或HHcy引起的PQC损伤的原因。因此,本综述基于细胞培养和实验动物模型,重点介绍了在细胞PQC的背景下对HHcy的当前理解及其病理生理和临床后果,表观基因组变化,B12的治疗意义以及化学分子伴侣。
更新日期:2019-06-30
中文翻译:
同型半胱氨酸在蛋白质质量控制过程中的意义。
同型半胱氨酸(Hcy)是蛋氨酸代谢过程中产生的关键代谢产物。血液中Hcy的升高水平被称为高同型半胱氨酸血症(HHcy)。HHcy是由叶酸或B12的新陈代谢不足/缺乏或Hcy代谢缺陷引起的。越来越多的证据表明,HHcy与心血管疾病和脑疾病有关,包括动脉粥样硬化,内皮损伤和中风等。维生素B12(钴胺素; B12)是两种代谢反应必不可少的水溶性维生素。它充当蛋氨酸合酶和L-甲基丙二酰-CoA突变酶的辅助因子。此外,它对于红细胞的DNA合成和成熟也至关重要。B12缺乏与血液和神经系统疾病有关。高同型半胱氨酸血症(HHcy)诱导的毒性被认为是由Hcy及其代谢产物(同型半胱氨酸化蛋白)的积累介导的。细胞蛋白质质量控制(PQC)对于维持蛋白质组完整性是必不可少的,而细胞生存力及其衰竭会导致多种疾病的发展。伴侣蛋白,未折叠蛋白应答(UPR),泛素-蛋白酶体系统(UPS)和自噬是PQC的类似策略,可维持细胞蛋白质组的完整性。最近,多项研究报道,HHcy通过降低分子伴侣水平,激活UPR和损害自噬来引起PQC的紊乱。此外,HHcy还诱导细胞毒性,炎症,蛋白质聚集和凋亡。已经显示出某些因素,包括SIRT1-HSF1轴的改变和蛋白质的不可逆同型半胱氨酸化,是造成叶酸和/或B12缺乏或HHcy引起的PQC损伤的原因。因此,本综述基于细胞培养和实验动物模型,重点介绍了在细胞PQC的背景下对HHcy的当前理解及其病理生理和临床后果,表观基因组变化,B12的治疗意义以及化学分子伴侣。