MRP1 mediates folate transport and antifolate sensitivity in Plasmodium falciparum

FEBS Lett. 2016 Feb;590(4):482-92. doi: 10.1002/1873-3468.12079. Epub 2016 Feb 17.

Abstract

Multidrug resistance-associated proteins (MRP) of Plasmodium falciparum have been associated with altered drug sensitivity. Knowledge on MRP substrate specificity is indispensible for the characterization of resistance mechanisms and identifying its physiological roles. An untargeted metabolomics approach detected decreased folate concentrations in red blood cells infected with schizont stage parasites lacking expression of MRP1. Furthermore, a tenfold decrease in sensitivity toward the folate analog methotrexate was detected for parasites lacking MRP1. PfMRP1 is involved in the export of folate from parasites into red blood cells and is therefore a relevant factor for efficient malaria treatment through the folate pathway.

Keywords: ABC transporter; Plasmodium falciparum; folate; multidrug resistance protein; multidrug resistance-associated proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Biological Transport
  • Drug Resistance, Multiple*
  • Erythrocytes / metabolism
  • Erythrocytes / parasitology
  • Folic Acid / metabolism*
  • Folic Acid Antagonists / chemistry
  • Folic Acid Antagonists / pharmacology*
  • Gene Knockout Techniques
  • Humans
  • Metabolomics
  • Methotrexate / chemistry
  • Methotrexate / pharmacology
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / metabolism*
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism*
  • Substrate Specificity

Substances

  • Antimalarials
  • Folic Acid Antagonists
  • Multidrug Resistance-Associated Proteins
  • Protozoan Proteins
  • Folic Acid
  • Methotrexate