Iron-sulfur flavoproteins (Isf) are flavin mononucleotide (FMN)- and FeS cluster-containing proteins commonly encountered in anaerobic prokaryotes. However, with the exception of Isf from Methanosarcina thermophila, which participates in oxidative stress management by removing oxygen and hydrogen peroxide, none of these proteins has been characterized in terms of function. Trichomonas vaginalis, a sexually transmitted eukaryotic parasite of humans, was found to express several iron-sulfur flavoprotein (TvIsf) homologs in its hydrogenosomes. We show here that in addition to having oxygen-reducing activity, the recombinant TvIsf also functions as a detoxifying reductase of metronidazole and chloramphenicol, both of which are antibiotics effective against a variety of anaerobic microbes. TvIsf can utilize both NADH and reduced ferredoxin as electron donors. Given the prevalence of Isf in anaerobic prokaryotes, we propose that these proteins are central to a novel defense mechanism against xenobiotics.
- MeSH
- antitrichomonádové látky farmakologie MeSH
- ferredoxiny metabolismus MeSH
- flavoproteiny metabolismus MeSH
- geny hub MeSH
- katalýza MeSH
- léková rezistence MeSH
- metronidazol chemie farmakologie MeSH
- molekulární sekvence - údaje MeSH
- NAD metabolismus MeSH
- proteiny obsahující železo a síru metabolismus MeSH
- sekvence aminokyselin MeSH
- subcelulární frakce účinky léků metabolismus MeSH
- Trichomonas vaginalis metabolismus MeSH
- vodík metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Clinical infectious diseases, ISSN 1058-4838 vol. 50, suppl. 1, February 2010
33 s. : il., tab. ; 28 cm
- MeSH
- antibakteriální látky MeSH
- antitrichomonádové látky MeSH
- bakteriální léková rezistence MeSH
- bakteriemie MeSH
- daptomycin aplikace a dávkování farmakokinetika terapeutické užití MeSH
- hemoragická septikemie MeSH
- infekce spojené se zdravotní péčí klasifikace MeSH
- methicilin rezistentní Staphylococcus aureus MeSH
- metronidazol terapeutické užití MeSH
- minocyklin MeSH
- mnohočetná bakteriální léková rezistence MeSH
- rizikové faktory MeSH
- Publikační typ
- sborníky MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- infekční lékařství
- O autorovi
- Tally, Francis P., 1940-2006 Autorita
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
