天津大学叶升课题组取得一项新突破。他们提出了人单羧酸转运蛋白的转运机制及药物发现。该项研究成果发表在2025年3月17日出版的《中国药理学报》上。

该研究团队以主成分分析为主题来阐明MCT家族的变构机制。增强采样显示，特定残基对（E46-K289和E376-R143）对于维持MCT1的内向和外向构象至关重要。量子化学计算和伞式采样表明，乳酸分子和质子是顺序共输的，其中K38和R313在乳酸易位中起关键作用。基于这些数据，研究小组开展了针对MCT1核心口袋的药物筛选活动，并确定水飞蓟宾是一种选择性MCT1抑制剂。水飞蓟宾对MCT1高表达的肿瘤细胞有明显的抑制作用。这些发现为全面了解MCT1的乳酸转运机制奠定了基础，为合理设计靶向MCT1的抗肿瘤药物奠定了基础。

据介绍，人单羧酸转运体（MCTs）对肿瘤细胞糖酵解至关重要。抑制MCT介导的乳酸转运可以抑制实体瘤的增殖，提高免疫系统对肿瘤的免疫效能。尽管这种转运体很重要，但MCT1转运乳酸的分子机制仍然不清楚，阻碍了靶向治疗的发展。

附：英文原文

Title: Transport mechanism and drug discovery of human monocarboxylate transporter 1

Author: Shi, Sai, Li, Jia-chen, Zhou, Xiao-yu, Li, Zhen-lu, Wang, Ya-xin, Xu, Bing-hong, Ye, Sheng

Issue&Volume: 2025-03-17

Abstract: Human monocarboxylate transporters (MCTs) are crucial for tumour cell glycolysis. Inhibiting MCT-mediated lactate transport can suppress the proliferation of solid tumours and enhance the efficacy of the immune system against tumours. Despite the importance of this transporter, the molecular mechanism of lactate transport by MCT1 remains elusive, hindering the development of targeted therapies. Here, we used principal component analysis to elucidate the allosteric mechanisms of the MCT family. Enhanced sampling revealed that specific residue pairs (E46-K289 and E376-R143) are essential for maintaining the inwards and outwards conformations of MCT1. Quantum chemical calculations and umbrella sampling demonstrated that lactate molecules and protons are co-transported sequentially, with K38 and R313 playing key roles in lactate translocation. On the basis of these data, we conducted a drug screening campaign targeting the core pocket of MCT1 and identified silybin as a selective MCT1 inhibitor. Silybin had significant inhibitory effects on tumour cells with high MCT1 expression. These findings provide a comprehensive understanding of the lactate transport mechanism of MCT1 and lay the groundwork for the rational design of antitumour drugs targeting MCT1.

DOI: 10.1038/s41401-025-01517-7

Source: https://www.nature.com/articles/s41401-025-01517-7