Pyruvate-ferredoxin oxidoreductase metronidazole

Samarawickrema NA, Brown DM, Upcroft JA, Thammapalerd N, Upcroft P (1997) Involvement of superoxide dismutase and pyruvate ferredoxin oxidoreductase in mechanisms of metronidazole resistance in Entamoeba histolytica. J Antimicrob Chemother 40 833-840... 

Though pyruvate ferredoxin oxidoreductase activates the prodrug metronidazole, it may not perform an essential function in the anaerobic parasites. The enzyme activity was significantly lower in metronidazole-resistant G lamblia. Some aerobic metronidazole-resistant Tvaginalis strains have no detectable pyruvate ferredoxin oxidoreductase activity but are viable. A knockdown of expression of this enzyme in G lamblia by ribozym e-anti sense chimeric RNA resulted in... 

The reaction is catalyzed by pyruvate ferredoxin oxidoreductase localized in the hydrogenosome, an organelle unique to trichomonads (see Chapter 3). Under physiological conditions, metronidazole undergoes further metabolism in trichomonads to... 

Anaerobic parasites, such as T. vaginalis and E. histolytica, lack functional mitochondria. Pyruvate generated by the glycolytic pathway is further metabolized within the cytosol of Giardia and Entamoeba species and in the hydrogenosome of these parasites, a subcellular organelle unique to trichomonads (4). Under anaerobic conditions, pyruvate is converted into acetyl Co-A and COj by pyruvateferredoxin oxidoreductase with the concomitant reduction of ferredoxin. Metronidazole and other nitro-imidazole derivatives are toxic to these anaerobes after reduction of the nitro moiety by ferredoxin. As these compounds are not reduced in mamalian cells, selectivity of their antiparasitic effects is assured (see Chapter 3). 

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