Biochemistry Division, National Institute of Nutrition, Hyderabad, India.
Department of Biological Sciences, BITS-Pilani, 500078, Hyderabad Campus, Hyderabad, Telangana, India.
Biochimie. 2019 Oct;165:19-31. doi: 10.1016/j.biochi.2019.06.017. Epub 2019 Jun 30.
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.
同型半胱氨酸（Hcy）是蛋氨酸代谢过程中产生的一种关键代谢产物。血液中 Hcy 水平升高称为高同型半胱氨酸血症（HHcy）。HHcy 是由于叶酸或 B12 代谢受损/缺乏或 Hcy 代谢缺陷引起的。越来越多的证据表明，HHcy 与心血管和脑部疾病有关，包括动脉粥样硬化、内皮损伤和中风等。维生素 B12（钴胺素；B12）是一种必需的水溶性维生素，对于两种代谢反应至关重要。它作为蛋氨酸合成酶和 L-甲基丙二酰辅酶 A 变位酶的辅助因子。此外，它对 DNA 合成和 RBC 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通过 Hcy 和其代谢物、同型半胱氨酸化蛋白的积累来介导的。细胞蛋白质质量控制（PQC）对于维持蛋白质组完整性、细胞活力及其失败对于多种疾病的发展至关重要。伴侣蛋白、未折叠蛋白反应（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 通过降低伴侣蛋白水平、激活 UPR 和损害自噬来负责 PQC 的失调。此外，HHcy 还会诱导细胞毒性、炎症、蛋白质聚集和细胞凋亡。已经表明，一些因素包括改变的 SIRT1-HSF1 轴和蛋白质的不可逆同型半胱氨酸化，是叶酸和/或 B12 缺乏或 HHcy 诱导的 PQC 损伤的原因。因此，本综述强调了 HHcy 在细胞 PQC 及其病理生理和临床后果、表观遗传变化、B12 的治疗意义以及基于细胞培养和实验动物模型的化学伴侣蛋白方面的当前认识。
