Nogueira Eugénia, Sárria Marisa P, Azoia Nuno G, Antunes Egipto, Loureiro Ana, Guimarães Diana, Noro Jennifer, Rollett Alexandra, Guebitz Georg, Cavaco-Paulo Artur
Centre of Biological Engineering , University of Minho , Campus of Gualtar , 4710-057 Braga , Portugal.
Centre of Molecular and Environmental Biology (CBMA), Department of Biology , University of Minho , Campus of Gualtar , 4710-057 Braga , Portugal.
Biochemistry. 2018 Dec 11;57(49):6780-6786. doi: 10.1021/acs.biochem.8b00607. Epub 2018 Nov 27.
The folate antagonist methotrexate is a cytotoxic drug used in the treatment of several cancer types. The entry of methotrexate into the cell is mediated by two main transport systems: the reduced folate carrier and membrane-associated folate receptors. These transporters differ considerably in their mechanism of (anti)folate uptake, substrate specificity, and tissue specificity. Although the mechanism of action of the reduced folate carrier is fairly well-established, that of the folate receptor has remained unknown. The development of specific folate receptor-targeted antifolates would be accelerated if additional mechanistic data were to become available. In this work, we used two fluorescently labeled conjugates of methotrexate, differently linked at the terminal groups, to clarify the uptake mechanism by folate receptor-α. The results demonstrate the importance of methotrexate amino groups in the interaction with folate receptor-α.
叶酸拮抗剂甲氨蝶呤是一种用于治疗多种癌症类型的细胞毒性药物。甲氨蝶呤进入细胞是由两个主要转运系统介导的：还原型叶酸载体和膜相关叶酸受体。这些转运体在（抗）叶酸摄取机制、底物特异性和组织特异性方面有很大差异。尽管还原型叶酸载体的作用机制已相当明确，但叶酸受体的作用机制仍不清楚。如果能获得更多的机制数据，靶向叶酸受体的特异性抗叶酸药物的研发将会加速。在这项研究中，我们使用了两种末端基团连接方式不同的甲氨蝶呤荧光标记共轭物，以阐明叶酸受体-α的摄取机制。结果证明了甲氨蝶呤氨基在与叶酸受体-α相互作用中的重要性。
