Journal
MOLECULAR AND BIOCHEMICAL PARASITOLOGY
Volume 170, Issue 2, Pages 108-111Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.molbiopara.2009.12.001
Keywords
Malaria; Isoprenoid biosynthesis; Drug targets
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Funding
- Child Health Research Center of Excellence in Developmental Biology at Washington University School of Medicine [K12-HD01487]
- Pediatric Infectious Diseases Society
- NIH [K08 AI079010]
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Novel antimalarial drugs are urgently needed to treat severe malaria caused by Plasmodium falciparum. Isoprenoid biosynthesis is a promising target pathway, since the biosynthetic route in Plasmodia is biochemically distinct from the mevalonate pathway in humans. The small molecule fosmidomycin is an inhibitor of the enzyme responsible for the first dedicated step in isoprenoid biosynthesis, deoxyxylulose 5-phosphate reductoisomerase (DXR). However, the antimalarial effects of fosmidomycin might not be specific to DXR inhibition and further validation of DXR is warranted. We present the first functional genetic validation of P. falciparum DXR (PF14_0641). Using a single cross-over strategy, we show that plasmid integration occurs at the DXR locus but only when DXR gene function is preserved, but not when integration disrupts gene function. These data indicate that DXR is required for intraerythrocytic development of P. falciparum. (C) 2009 Elsevier B.V. All rights reserved.
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