Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPAZ), Paseo de la Castellana 261, 28046, Madrid, Spain; Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, 28029, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.
Laboratory of Cardiovascular Proteomics, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández de Almagro 3, 28029, Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
Biochimie. 2020 Jun;173:33-47. doi: 10.1016/j.biochi.2020.02.015. Epub 2020 Feb 24.
Enzymes of the methionine and homocysteine metabolism catalyze reactions belonging to the methionine and folate cycles and the transsulfuration pathway. The importance of the metabolites produced through these routes (e.g. S-adenosylmethionine, homocysteine) and their role in e.g. epigenetics or redox mechanisms makes their tight regulation essential for a correct cellular function. Pharmacological or pathophysiological insults induce, among others, changes in activity, oligomerization, protein levels, subcellular localization and expression of these enzymes. The abundance of these proteins in liver has made this organ the preferred system to study their regulation. Nevertheless, knowledge about their putative protein-protein interactions is limited in this and other tissues and cell types. High-throughput methods, including immunoprecipitation, affinity purification coupled to mass spectrometry and yeast two-hybrid have rendered the identification of a number of protein-protein interactions involving these enzymes in several systems. Validation by coimmunoprecipitation and/or pull-down has been made, mainly, after coexpression of bait and prey, but few of the interactions have been confirmed. Additionally, information concerning the role of these interactions in the regulation of this pathway and other cellular processes is scarce. Here, we review the current knowledge on mammalian protein-protein interactions involving methionine adenosyltransferases, S-adenosylhomocysteine hydrolase, betaine homocysteine S-methyltransferases, methionine synthase and cystathionine β-synthase, although references to data obtained in other organisms are also made. Moreover, the verified or putative implication of these interactions in the regulation of methionine and homocysteine metabolism, its interplay with other metabolic pathways and its putative link to pathophysiological processes, such as oncogenesis, is discussed.
蛋氨酸和同型半胱氨酸代谢的酶催化属于蛋氨酸和叶酸循环以及转硫途径的反应。通过这些途径产生的代谢物（例如 S-腺苷甲硫氨酸、同型半胱氨酸）的重要性及其在表观遗传学或氧化还原机制中的作用使得它们的紧密调节对于正确的细胞功能至关重要。药理学或病理生理学的刺激除其他外，会引起这些酶的活性、寡聚化、蛋白质水平、亚细胞定位和表达的变化。这些蛋白质在肝脏中的丰富程度使得该器官成为研究其调节的首选系统。然而，关于这些酶在其他组织和细胞类型中的假定蛋白-蛋白相互作用的知识是有限的。包括免疫沉淀、亲和纯化与质谱联用和酵母双杂交在内的高通量方法已经鉴定出了几种涉及这些酶的蛋白质-蛋白质相互作用在几个系统中。通过共免疫沉淀和/或下拉实验进行了验证，主要是在诱饵和猎物共表达之后，但很少有相互作用得到证实。此外，关于这些相互作用在该途径和其他细胞过程的调节中的作用的信息也很少。在这里，我们综述了关于涉及蛋氨酸腺苷转移酶、S-腺苷同型半胱氨酸水解酶、甜菜碱同型半胱氨酸 S-甲基转移酶、蛋氨酸合成酶和胱硫醚β-合酶的哺乳动物蛋白-蛋白相互作用的最新知识，尽管也提到了在其他生物体中获得的数据。此外，还讨论了这些相互作用在蛋氨酸和同型半胱氨酸代谢的调节中的验证或假定的作用，及其与其他代谢途径的相互作用及其与病理生理过程（如癌发生）的潜在联系。
