Dihydroxyacetone and methylglyoxal as permeants of the Plasmodium aquaglyceroporin inhibit parasite proliferation.
The aquaglyceroporin of Plasmodium falciparum (PfAQP) is a bi-functional channel with permeability for water and solutes. Its functions supposedly are in osmotic protection of parasites and in facilitation of glycerol permeation for glycerolipid biosynthesis. Here, we show PfAQP permeability for the glycolysis-related metabolites methylglyoxal, a cytotoxic byproduct, and dihydroxyacetone, a ketotriose. AQP3, the red cell aquaglyceroporin, also passed dihydroxacetone but excluded methylglyoxal. Proliferation of malaria parasites was inhibited by methylglyoxal with an IC50 around 200 microM. Surprisingly, also dihydroxyacetone, which is an energy source in human cells, was antiproliferative in chloroquine-sensitive and resistant strains with an IC50 around 3 mM. We expressed P. falciparum glyceraldehyde 3-phosphate dehydrogenase (PfGAPDH) to examine whether it is inhibited by either carbonyl compound. Methylglyoxal did not affect PfGAPDH on incubation with 2.5 mM for 20 h. Treatment with 2.5 mM dihydroxyacetone, however, abolished PfGAPDH activity within 6 h. Aquaglyceroporin permeability for glycolytic metabolites may thus be of physiological significance.
Pavlovic-Djuranovic
Slavica
S
Department of Pharmaceutical Biochemistry, University of Tübingen, Morgenstelle 8, D-72076 Tübingen, Germany.
Kun
Jürgen F J
JF
Schultz
Joachim E
JE
Beitz
Eric
E
D000818:Animals; D051400:Aquaporin 3 / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004098:Dihydroxyacetone / Q000494:pharmacology*; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000037:antagonists & inhibitors / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D018272:Porins / Q000378:metabolism*; D015800:Protozoan Proteins / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000494:pharmacology*; D051381:Rats; D014982:Xenopus laevis
C496029:Aqp3 protein, rat; C449801:PfAQP protein, Plasmodium falciparum; D018272:Porins; D015800:Protozoan Proteins; D051400:Aquaporin 3; D011765:Pyruvaldehyde; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D004098:Dihydroxyacetone; D005990:Glycerol