Functional genetic analysis of the Plasmodium falciparum deoxyxylulose 5-phosphate reductoisomerase gene

Mol Biochem Parasitol. 2010 Apr;170(2):108-11. doi: 10.1016/j.molbiopara.2009.12.001. Epub 2009 Dec 16.

Abstract

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.

Keywords: Isoprenoid biosynthesis; Malaria; drug targets.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aldose-Ketose Isomerases / genetics*
  • Aldose-Ketose Isomerases / physiology
  • Animals
  • Erythrocytes / parasitology*
  • Genes, Essential
  • Genes, Protozoan
  • Humans
  • Multienzyme Complexes / genetics*
  • Multienzyme Complexes / physiology
  • Mutagenesis, Insertional
  • Oxidoreductases / genetics*
  • Oxidoreductases / physiology
  • Plasmids
  • Plasmodium falciparum / enzymology*
  • Plasmodium falciparum / growth & development
  • Protozoan Proteins / genetics*
  • Protozoan Proteins / physiology

Substances

  • Multienzyme Complexes
  • Protozoan Proteins
  • Oxidoreductases
  • 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • Aldose-Ketose Isomerases