The inhibition of pyruvate transport across the plasma membrane of the bloodstream form of Trypanosoma brucei and its metabolic implications.
The pyruvate produced by glycolysis in the bloodstream form of the trypanosome is excreted into the host bloodstream by a facilitated diffusion carrier. The sensitivity of pyruvate transport for alpha-cyano-4-hydroxycinnamate and the compound UK5099 [alpha-cyano-beta-(1-phenylindol-3-yl)acrylate], which are known to be selective inhibitors of pyruvate (monocarboxylate) transporters present in mitochondria and the plasma membrane of eukaryotic cells, was examined. The trypanosomal pyruvate carrier was found to be rather insensitive to inhibition by alpha-cyano-4-hydroxycinnamate (Ki = 17 mM) but could be completely blocked by UK5099 (Ki = 49 microM). Inhibition of pyruvate transport resulted in the retention, and concomitant accumulation, of pyruvate within the trypanosomes, causing acidification of the cytosol and osmotic destabilization of the cells. Our results indicate that this physiological state has serious metabolic consequences and ultimately leads to cell death; thereby identifying the pyruvate carrier as a possible target for chemotherapeutic intervention.
Wiemer
E A
EA
Research Unit for Tropical Diseases, International Institute of Cellular and Molecular Pathology, Brussels, Belgium.
Michels
P A
PA
Opperdoes
F R
FR
D000179:Acrylates / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001769:Blood / Q000469:parasitology; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D006019:Glycolysis; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D027501:Monocarboxylic Acid Transporters; D011773:Pyruvates / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000070590:Solute Carrier Proteins; D014346:Trypanosoma brucei brucei / Q000378:metabolism* / Q000472:pathogenicity
D000179:Acrylates; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D027501:Monocarboxylic Acid Transporters; C000629174:Mpc1 protein, rat; D011773:Pyruvates; D000070590:Solute Carrier Proteins; C043654:2-cyano-3-(1-phenylindol-3-yl)acrylate