Effect of fosmidomycin on metabolic and transcript profiles of the methylerythritol phosphate pathway in Plasmodium falciparum

Memórias do Instituto Oswaldo Cruz

María B Cassera¹  Emilio F Merino¹  Valnice J Peres²  Emilia A Kimura²  Gerhard Wunderlich²  Alejandro M Katzin² 

[1] ,Universidade de São Paulo Instituto Ciências Biomédicas Departamento de ParasitologiaSão Paulo SP ,Brasil

关键词: Plasmodium falciparum;    malaria;    fosmidomycin;    isoprenoid biosynthesis;    real time polymerase chain reaction;   

DOI  :  10.1590/S0074-02762007000300019

来源: SciELO

【 摘 要 】

In Plasmodium falciparum, the formation of isopentenyl diphosphate and dimethylallyl diphosphate, central intermediates in the biosynthesis of isoprenoids, occurs via the methylerythritol phosphate (MEP) pathway. Fosmidomycin is a specific inhibitor of the second enzyme of the MEP pathway, 1-deoxy-D-xylulose-5-phosphate reductoisomerase. We analyzed the effect of fosmidomycin on the levels of each intermediate and its metabolic requirement for the isoprenoid biosynthesis, such as dolichols and ubiquinones, throughout the intraerythrocytic cycle of P. falciparum. The steady-state RNA levels of the MEP pathway-associated genes were quantified by real-time polymerase chain reaction and correlated with the related metabolite levels. Our results indicate that MEP pathway metabolite peak precede maximum transcript abundance during the intraerythrocytic cycle. Fosmidomycin-treatment resulted in a decrease of the intermediate levels in the MEP pathway as well as in ubiquinone and dolichol biosynthesis. The MEP pathway associated transcripts were modestly altered by the drug, indicating that the parasite is not strongly responsive at the transcriptional level. This is the first study that compares the effect of fosmidomycin on the metabolic and transcript profiles in P. falciparum, which has only the MEP pathway for isoprenoid biosynthesis.

【 授权许可】

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