TY - JOUR
T1 - Functional genetic analysis of the Plasmodium falciparum deoxyxylulose 5-phosphate reductoisomerase gene
AU - Odom, Audrey R.
AU - Van Voorhis, Wesley C.
N1 - Funding Information:
We thank Dr. David Fidock, Columbia University, for the gift of the plasmids and helpful advice on the knockout strategy. We also wish to thank Lynn Barrett, laboratory manager, and Kasey Rivas for technical support, and we thank Drs. Daniel Goldberg, Gregory Storch, and Phillip Tarr, Washington University, for critical reading of this manuscript. Dr. Odom is a Scholar of the Child Health Research Center of Excellence in Developmental Biology at Washington University School of Medicine (K12-HD01487), and this work was supported by a Pediatric Infectious Diseases Society Fellowship (Dr. Odom) and NIH K08 AI079010 (Dr. Odom).
PY - 2010/4
Y1 - 2010/4
N2 - 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.
AB - 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.
KW - Drug targets
KW - Isoprenoid biosynthesis
KW - Malaria
UR - http://www.scopus.com/inward/record.url?scp=74849090103&partnerID=8YFLogxK
U2 - 10.1016/j.molbiopara.2009.12.001
DO - 10.1016/j.molbiopara.2009.12.001
M3 - Article
C2 - 20018214
AN - SCOPUS:74849090103
SN - 0166-6851
VL - 170
SP - 108
EP - 111
JO - Molecular and Biochemical Parasitology
JF - Molecular and Biochemical Parasitology
IS - 2
ER -