1 Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas (CSIC) , Madrid, Spain .
2 Molecular Hepatology Group, Instituto de Investigación Sanitaria La Paz (IdiPAZ) , Madrid, Spain .
Antioxid Redox Signal. 2018 Aug 1;29(4):408-452. doi: 10.1089/ars.2017.7237. Epub 2018 Jan 9.
Transsulfuration allows conversion of methionine into cysteine using homocysteine (Hcy) as an intermediate. This pathway produces S-adenosylmethionine (AdoMet), a key metabolite for cell function, and provides 50% of the cysteine needed for hepatic glutathione synthesis. The route requires the intake of essential nutrients (e.g., methionine and vitamins) and is regulated by their availability. Transsulfuration presents multiple interconnections with epigenetics, adenosine triphosphate (ATP), and glutathione synthesis, polyol and pentose phosphate pathways, and detoxification that rely mostly in the exchange of substrates or products. Major hepatic diseases, rare diseases, and sensorineural disorders, among others that concur with oxidative stress, present impaired transsulfuration. Recent Advances: In contrast to the classical view, a nuclear branch of the pathway, potentiated under oxidative stress, is emerging. Several transsulfuration proteins regulate gene expression, suggesting moonlighting activities. In addition, abnormalities in Hcy metabolism link nutrition and hearing loss.
Knowledge about the crossregulation between pathways is mostly limited to the hepatic availability/removal of substrates and inhibitors. However, advances regarding protein-protein interactions involving oncogenes, identification of several post-translational modifications (PTMs), and putative moonlighting activities expand the potential impact of transsulfuration beyond methylations and Hcy.
Increasing the knowledge on transsulfuration outside the liver, understanding the protein-protein interaction networks involving these enzymes, the functional role of their PTMs, or the mechanisms controlling their nucleocytoplasmic shuttling may provide further insights into the pathophysiological implications of this pathway, allowing design of new therapeutic interventions. Antioxid. Redox Signal. 29, 408-452.
转硫途径允许使用同型半胱氨酸 (Hcy) 作为中间产物将蛋氨酸转化为半胱氨酸。该途径产生 S-腺苷甲硫氨酸 (AdoMet)，这是细胞功能的关键代谢物，并提供肝脏谷胱甘肽合成所需半胱氨酸的 50%。该途径需要摄入必需营养素（例如蛋氨酸和维生素），并受其可用性的调节。转硫途径与表观遗传学、三磷酸腺苷 (ATP) 和谷胱甘肽合成、多元醇和戊糖磷酸途径以及解毒作用之间存在多种相互联系，这些联系主要依赖于底物或产物的交换。多种主要肝脏疾病、罕见疾病和感觉神经性疾病，以及与氧化应激相关的疾病，都存在转硫途径受损的情况。
与经典观点相反，在氧化应激下增强的途径的核分支正在出现。几种转硫蛋白调节基因表达，表明存在兼职活动。此外，Hcy 代谢异常与营养和听力损失有关。
关于途径之间的交叉调节的知识主要限于肝脏中底物和抑制剂的可用性/去除。然而，涉及癌基因的蛋白质-蛋白质相互作用、鉴定几种翻译后修饰 (PTM) 和潜在的兼职活动方面的进展，扩大了转硫途径超出甲基化和 Hcy 的潜在影响。
增加对肝脏以外的转硫途径的了解、理解涉及这些酶的蛋白质-蛋白质相互作用网络、它们的 PTM 的功能作用或控制其核质穿梭的机制，可能会深入了解该途径的病理生理意义，从而设计新的治疗干预措施。抗氧化。氧化还原信号。29,408-452。
