Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.
Curr Opin Struct Biol. 2022 Jun;74:102353. doi: 10.1016/j.sbi.2022.102353. Epub 2022 Mar 16.
Structural studies on mammalian vitamin transport lag behind other metabolites. Folates, also known as B9 vitamins, are essential cofactors in one-carbon transfer reactions in biology. Three different systems control folate uptake in the human body; folate receptors function to capture and internalise extracellular folates via endocytosis, whereas two major facilitator superfamily transporters, the reduced folate carrier (RFC; SLC19A1) and proton-coupled folate transporter (PCFT; SLC46A1) control the transport of folates across cellular membranes. Targeting specific folate transporters is being pursued as a route to developing new antifolates with improved pharmacology. Recent structures of the proton-coupled folate transporter, PCFT, revealed key insights into antifolate recognition and the mechanism of proton-coupled transport. Combined with previously determined structures of folate receptors and new predictions for the structure of the RFC, we are now able to develop a structure-based understanding of folate and antifolate recognition to accelerate efforts in antifolate drug development.
哺乳动物维生素转运的结构研究落后于其他代谢物。叶酸，也称为 B9 维生素，是生物学中一碳转移反应的必需辅助因子。人体中有三种不同的系统控制叶酸的摄取；叶酸受体通过内吞作用捕获和内化细胞外叶酸，而两个主要的易化剂超家族转运蛋白，还原叶酸载体（RFC；SLC19A1）和质子偶联叶酸转运蛋白（PCFT；SLC46A1）控制叶酸穿过细胞膜的转运。靶向特定的叶酸转运蛋白被认为是开发具有改善药理学的新型抗叶酸药物的一种途径。最近质子偶联叶酸转运蛋白 PCFT 的结构揭示了对抗叶酸识别和质子偶联转运机制的关键见解。结合先前确定的叶酸受体结构和 RFC 的新预测结构，我们现在能够基于结构理解叶酸和抗叶酸的识别，以加速抗叶酸药物开发的努力。
