A systematic approach to understand the mechanism of action of the bisthiazolium compound T4 on the human malaria parasite, Plasmodium falciparum
| Autor: | Jacques Prudhomme, Henri Vial, Choukri Ben Mamoun, Hugues Ahiboh, Jeffrey R. Johnson, Karine G. Le Roch, Kerstin Henson, David Plouffe, William H. Witola, Elizabeth A. Winzeler, John R. Yates, Duk Won D. Chung, Yingyao Zhou |
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| Přispěvatelé: | instituto Geofísico, Escuela Politécnica Nacional (EPN), British Antarctic Survey (BAS), Natural Environment Research Council (NERC), J Craig Venter Institute, J. Craig Venter Institute, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Cold and Arid Regions Environmental and Engineering Research Institute, Chinese Academy of Sciences [Beijing] (CAS), Department of Ecology and Evolutionary Biology, University of Kansas [Lawrence] (KU), Ningbo Institute of Technology (NIT), Department of Molecular Biology [San Diego], The Scripps Research Institute [La Jolla], University of California [San Diego] (UC San Diego), University of California-University of California-University of California [San Diego] (UC San Diego), University of California-University of California, Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Dynamique moléculaire des interactions membranaires (DMIM), Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2) |
| Rok vydání: | 2008 |
| Předmět: |
Erythrocytes
Proteome Transcription Genetic Transferases (Other Substituted Phosphate Groups) MESH: Cell Cycle Drug resistance Medical and Health Sciences Choline Transcriptome chemistry.chemical_compound Tandem Mass Spectrometry MESH: Reverse Transcriptase Polymerase Chain Reaction 2.2 Factors relating to the physical environment Parasite hosting MESH: Animals Aetiology MESH: Plasmodium falciparum Cells Cultured Oligonucleotide Array Sequence Analysis 0303 health sciences Cultured Reverse Transcriptase Polymerase Chain Reaction MESH: Erythrocytes Cell Cycle MESH: Choline Biological Sciences 3. Good health MESH: Proteome Infectious Diseases Biochemistry 5.1 Pharmaceuticals Ethanolamines Protozoan Phosphatidylcholines MESH: RNA Protozoan Development of treatments and therapeutic interventions medicine.symptom Infection Transcription Algorithms RNA Protozoan Biotechnology MESH: Cells Cultured Research Article lcsh:QH426-470 Bioinformatics lcsh:Biotechnology Cells Plasmodium falciparum MESH: Thiazoles MESH: Algorithms Biology MESH: Ethanolamines 03 medical and health sciences MESH: Gene Expression Profiling Antimalarials Rare Diseases Genetic Transferases Phosphatidylcholine lcsh:TP248.13-248.65 Information and Computing Sciences Genetics medicine Animals Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Nutrition 030304 developmental biology MESH: Humans 030306 microbiology MESH: Transcription Genetic Gene Expression Profiling MESH: Tandem Mass Spectrometry Lipid metabolism MESH: Phosphatidylcholines biology.organism_classification MESH: Antimalarials Malaria Vector-Borne Diseases lcsh:Genetics Thiazoles Good Health and Well Being chemistry Mechanism of action MESH: Oligonucleotide Array Sequence Analysis RNA MESH: Transferases (Other Substituted Phosphate Groups) |
| Zdroj: | BMC Genomics BMC Genomics, BioMed Central, 2008, 9, pp.513. ⟨10.1186/1471-2164-9-513⟩ BMC genomics, vol 9, iss 1 BMC Genomics, Vol 9, Iss 1, p 513 (2008) |
| ISSN: | 1471-2164 |
| DOI: | 10.1186/1471-2164-9-513⟩ |
| Popis: | Background In recent years, a major increase in the occurrence of drug resistant falciparum malaria has been reported. Choline analogs, such as the bisthiazolium T4, represent a novel class of compounds with strong potency against drug sensitive and resistant P. falciparum clones. Although T4 and its analogs are presumed to target the parasite's lipid metabolism, their exact mechanism of action remains unknown. Here we have employed transcriptome and proteome profiling analyses to characterize the global response of P. falciparum to T4 during the intraerythrocytic cycle of this parasite. Results No significant transcriptional changes were detected immediately after addition of T4 despite the drug's effect on the parasite metabolism. Using the Ontology-based Pattern Identification (OPI) algorithm with an increased T4 incubation time, we demonstrated cell cycle arrest and a general induction of genes involved in gametocytogenesis. Proteomic analysis revealed a significant decrease in the level of the choline/ethanolamine-phosphotransferase (PfCEPT), a key enzyme involved in the final step of synthesis of phosphatidylcholine (PC). This effect was further supported by metabolic studies, which showed a major alteration in the synthesis of PC from choline and ethanolamine by the compound. Conclusion Our studies demonstrate that the bisthiazolium compound T4 inhibits the pathways of synthesis of phosphatidylcholine from choline and ethanolamine in P. falciparum, and provide evidence for post-transcriptional regulations of parasite metabolism in response to external stimuli. |
| Databáze: | OpenAIRE |
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