A Key Role for Old Yellow Enzyme in the Metabolism of Drugs by Trypanosoma cruzi
| Autor: | Shunichi Fukuzumi, Bruno Kilunga Kubata, Toshihiko Maruyama, Samuel K. Martin, Michael Duszenko, Kei Ohkubo, Zakayi Kabututu, Tomoyoshi Nozaki, Michael Lazarus, Yoshihiro Urade, Craig Joe Munday |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Trypanosoma cruzi
Indomethacin Molecular Sequence Data Immunology Gene Expression Reductase Biology Dinoprost Catalysis Dinoprostone Article PG production chemistry.chemical_compound Menadione medicine Animals Immunology and Allergy Cyclooxygenase Inhibitors Amino Acid Sequence Nifurtimox Trypanocidal agent chemistry.chemical_classification Aspirin Base Sequence Sequence Homology Amino Acid Prostaglandin D2 Anti-Inflammatory Agents Non-Steroidal NADPH Dehydrogenase redox cycling DNA Protozoan biology.organism_classification Trypanocidal Agents Chagas' disease enzyme chagasic drug reduction Enzyme Mechanism of action chemistry Biochemistry Hydroxyprostaglandin Dehydrogenases medicine.symptom Oxidation-Reduction Drug metabolism Naphthoquinones medicine.drug |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.20020885 |
| Popis: | 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(2alpha) 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 PGH(2) to PGF(2alpha) 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 beta-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. |
| Databáze: | OpenAIRE |
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