Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission
| Autor: | Dennis R. Voelker, William H. Witola, Erol Fikrig, April M. Bobenchik, Aprajita Garg, Sahar Usmani-Brown, David A. Fidock, Choukri Ben Mamoun, Swapna Samanta, Jae Yeon Choi, Sophie H. Adjalley, Niseema Pachikara, Yang O. Zhao, Albert S. Lee, Laura Nic Lochlainn, Yoann Augagneur |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Plasmodium falciparum Fluorescent Antibody Technique Plasmodium Antimalarials parasitic diseases Reproduction Asexual medicine Gametocyte Serine Parasite hosting Humans Enzyme Inhibitors Malaria Falciparum Radiometry Multidisciplinary biology Anopheles Methyltransferases Biological Sciences biology.organism_classification medicine.disease Virology In vitro Complementation Female Malaria |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 110(45) |
| ISSN: | 1091-6490 |
| Popis: | Efficient transmission of Plasmodium species between humans and Anopheles mosquitoes is a major contributor to the global burden of malaria. Gametocytogenesis, the process by which parasites switch from asexual replication within human erythrocytes to produce male and female gametocytes, is a critical step in malaria transmission and Plasmodium genetic diversity. Nothing is known about the pathways that regulate gametocytogenesis and only few of the current drugs that inhibit asexual replication are also capable of inhibiting gametocyte development and blocking malaria transmission. Here we provide genetic and pharmacological evidence indicating that the pathway for synthesis of phosphatidylcholine in Plasmodium falciparum membranes from host serine is essential for parasite gametocytogenesis and malaria transmission. Parasites lacking the phosphoethanolamine N-methyltransferase enzyme, which catalyzes the limiting step in this pathway, are severely altered in gametocyte development, are incapable of producing mature-stage gametocytes, and are not transmitted to mosquitoes. Chemical screening identified 11 inhibitors of phosphoethanolamine N-methyltransferase that block parasite intraerythrocytic asexual replication and gametocyte differentiation in the low micromolar range. Kinetic studies in vitro as well as functional complementation assays and lipid metabolic analyses in vivo on the most promising inhibitor NSC-158011 further demonstrated the specificity of inhibition. These studies set the stage for further optimization of NSC-158011 for development of a class of dual activity antimalarials to block both intraerythrocytic asexual replication and gametocytogenesis. |
| Databáze: | OpenAIRE |
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