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A Key Role for Old Yellow Enzyme in the Metabolism of Drugs by Trypanosoma cruzi

Bruno Kilunga Kubata¹, Zakayi Kabututu^1,2, Tomoyoshi Nozaki³, Craig J. Munday¹, Shunichi Fukuzumi⁴, Kei Ohkubo⁴, Michael Lazarus¹, Toshihiko Maruyama¹, Samuel K. Martin⁵, Michael Duszenko⁶ and Yoshihiro Urade¹

¹ Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan
² Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
³ Department of Parasitology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
⁴ Department of Material and Life Science, Graduate School of Engineering, Osaka University, Core Research and Evolutional Science and Technology, JAPAN Science and Technology Corporation, Osaka 565-0871, Japan
⁵ United States Army Medical Research Unit-Kenya, Unit 64109, Army Post Office AE 09831-64109
⁶ Physiologisch-chemisches Institut der Universität Tübingen, 72076 Tübingen, Germany

Address correspondence to Bruno Kilunga Kubata, Department of Molecular Behavioral Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan. Phone: 81-6-6872-4851; Fax: 81-6-6872-2841; E-mail: kubata{at}obi.or.jp

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) F₂ 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 PGF₂ 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 ß-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 drug-metabolizing enzyme by which quinone drugs have their mechanism of action.

Key Words: Chagas' disease • enzyme • chagasic drug reduction • redox cycling • PG production

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