期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：11
页码：3356-3361
DOI：10.1073/pnas.1417102112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMalaria caused by Plasmodium falciparum is a severe infectious disease with high mortality and morbidity rates worldwide. Chloroquine (CQ) is a widely used antimalarial agent, but the emergence and spread of CQ-resistant parasites is a growing global health problem. Although its physiological relevance remains unknown, P. falciparum CQ resistance transporter (PfCRT) confers CQ resistance through CQ egress from digestive vacuoles of P. falciparum. To address this issue, recombinant CQ-sensitive or CQ-resistant PfCRT proteins were purified and their transport activities were assessed. Both CQ-sensitive and CQ-resistant PfCRTs transported CQ, various antimalarial agents, and basic amino acids, indicating that PfCRT is a polyspecific drug and nutrient exporter. Extrusion of chloroquine (CQ) from digestive vacuoles through the Plasmodium falciparum CQ resistance transporter (PfCRT) is essential to establish CQ resistance of the malaria parasite. However, the physiological relevance of PfCRT and how CQ-resistant PfCRT gains the ability to transport CQ remain unknown. We prepared proteoliposomes containing purified CQ-sensitive and CQ-resistant PfCRTs and measured their transport activities. All PfCRTs tested actively took up tetraethylammonium, verapamil, CQ, basic amino acids, polypeptides, and polyamines at the expense of an electrochemical proton gradient. CQ-resistant PfCRT exhibited decreased affinity for CQ, resulting in increased CQ uptake. Furthermore, CQ competitively inhibited amino acid transport. Thus, PfCRT is a H+-coupled polyspecific nutrient and drug exporter.
