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研究揭示PCFT识别和转运叶酸拮抗剂的结构基础
2021-05-30 21:08

英国牛津大学Simon Newstead等研究人员合作揭示PCFT识别和转运叶酸拮抗剂的结构基础。2021年5月26日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员表示,叶酸(也称为维生素 B9)作为合成核酸、氨基酸和通用甲基化试剂S-腺苷酸甲硫氨酸的起点,在细胞代谢中起着至关重要的作用。叶酸缺乏与许多发育、免疫和神经系统疾病有关。哺乳动物不能从头合成叶酸;因此,一些系统已经进化为从饮食中摄取叶酸并将它们分布在体内。

质子偶联的叶酸转运蛋白(PCFT,也称为SLC46A1)介导通过肠道刷状缘膜和脉络膜丛的叶酸摄取,并且是在癌症化疗中递送抗叶酸药物的重要途径。PCFT如何识别叶酸或抗叶酸剂目前尚不清楚。

研究人员报道了处于无底物状态以及与新一代抗叶酸药物(培美曲塞)复合的PCFT冷冻电镜结构。这些结果为理解抗叶酸识别提供了结构基础,并揭示了PCFT介导叶酸转运的pH调节机制。

附:英文原文

Title: Structural basis of antifolate recognition and transport by PCFT

Author: Joanne L. Parker, Justin C. Deme, Gabriel Kuteyi, Zhiyi Wu, Jiandong Huo, I. David Goldman, Raymond J. Owens, Philip C. Biggin, Susan M. Lea, Simon Newstead

Issue&Volume: 2021-05-26

Abstract: Folates (also known as vitamin B9) have a critical role in cellular metabolism as the starting point in the synthesis of nucleic acids, amino acids and the universal methylating agent S-adenylsmethionine1,2. Folate deficiency is associated with a number of developmental, immune and neurological disorders3,4,5. Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body3,6. The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus4,7, and is an important route for the delivery of antifolate drugs in cancer chemotherapy8,9,10. How PCFT recognizes folates or antifolate agents is currently unclear. Here we present cryo-electron microscopy structures of PCFT in a substrate-free state and in complex with a new-generation antifolate drug (pemetrexed). Our results provide a structural basis for understanding antifolate recognition and provide insights into the pH-regulated mechanism of folate transport mediated by PCFT.

DOI: 10.1038/s41586-021-03579-z

Source: https://www.nature.com/articles/s41586-021-03579-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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