Metronidazole and related 5-nitroimidazoles are the only available drugs in the treatment of human urogenital trichomoniasis caused by the protozoan parasite Trichomonas vaginalis. The drugs are activated to cytotoxic anion radicals by their reduction within the hydrogenosomes. It has been established that electrons required for metronidazole activation are released from pyruvate by the activity of pyruvate:ferredoxin oxidoreductase and transferred to the drug by a low-redox-potential carrier, ferredoxin. Here we describe a novel pathway involved in the drug activation within the hydrogenosome. The source of electrons is malate, another major hydrogenosomal substrate, which is oxidatively decarboxylated to pyruvate and CO2 by NAD-dependent malic enzyme. The electrons released during this reaction are transferred from NADH to ferredoxin by NADH dehydrogenase homologous to the catalytic module of mitochondrial complex I, which uses ferredoxin as electron acceptor. Trichomonads acquire high-level metronidazole resistance only after both pyruvate- and malate-dependent pathways of metronidazole activation are eliminated from the hydrogenosomes.
- MeSH
- antitrichomonádové látky farmakologie metabolismus MeSH
- lidé MeSH
- metronidazol farmakologie metabolismus MeSH
- organely metabolismus MeSH
- Trichomonas vaginalis metabolismus růst a vývoj účinky léků MeSH
- Tritrichomonas foetus metabolismus růst a vývoj účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- MeSH
- abnormality vyvolané léky etiologie MeSH
- embryo savčí účinky léků MeSH
- karcinogeny toxicita MeSH
- lidé MeSH
- metronidazol farmakokinetika metabolismus toxicita MeSH
- mutageny toxicita MeSH
- poškození DNA MeSH
- těhotenství MeSH
- testy genotoxicity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- ketonoxidoreduktasy metabolismus MeSH
- kyslík metabolismus MeSH
- laktátdehydrogenasy metabolismus MeSH
- léková rezistence MeSH
- lidé MeSH
- lyofilizace MeSH
- metronidazol farmakologie metabolismus MeSH
- Trichomonas vaginalis enzymologie metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
