A key role for old yellow enzyme in the metabolism of drugs by Trypanosoma cruzi

Bruno Kilunga Kubata, Zakayi Kabututu, Tomoyoshi Nozaki, Craig J. Munday, Shunichi Fukuzumi, Kei Ohkubo, Michael Lazarus, Toshihiko Maruyama, Samuel K. Martin, Michael Duszenko, Yoshihiro Urade

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Trypanosoma cruzi is the etiological agent of Chagas' disease. So far, first choice anti-chagasic drugs in use have been shown to have undesirable side effects in addition to the emergence of parasite resistance and the lack of prospect for vaccine against T. cruzi infection. Thus, the isolation and characterization of molecules essential in parasite metabolism of the anti-chagasic drugs are fundamental for the development of new strategies for rational drug design and/or the improvement of the current chemotherapy. While searching for a prostaglandin (PG) F synthase homologue, we have identified a novel "old yellow enzyme" from T. cruzi (TcOYE), cloned its cDNA, and overexpressed the recombinant enzyme. Here, we show that TcOYE reduced 9,11-endoperoxide PGH2 to PGF as well as a variety of trypanocidal drugs. By electron spin resonance experiments, we found that TcOYE specifically catalyzed one-electron reduction of menadione and β-lapachone to semiquinone-free radicals with concomitant generation of superoxide radical anions, while catalyzing solely the two-electron reduction of nifurtimox and 4-nitroquinoline-N-oxide drugs without free radical production. Interestingly, immunoprecipitation experiments revealed that anti-TcOYE polyclonal antibody abolished major reductase activities of the lysates toward these drugs, identifying TcOYE as a key drugmetabolizing enzyme by which quinone drugs have their mechanism of action.

Original languageEnglish
Pages (from-to)1241-1251
Number of pages11
JournalJournal of Experimental Medicine
Issue number9
StatePublished - 4 Nov 2002


  • Chagas' disease
  • Chagasic drug reduction
  • Enzyme
  • PG production
  • Redox cycling


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