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Originally published In Press as doi:10.1074/jbc.M110751200 on January 31, 2002

J. Biol. Chem., Vol. 277, Issue 15, 12824-12829, April 12, 2002
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The Antituberculosis Drug Ethionamide Is Activated by a Flavoprotein Monooxygenase*

Tommaso A. VannelliDagger , Alina DykmanDagger , and Paul R. Ortiz de Montellano§

From the Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143-0446

Ethionamide (ETA), a prodrug that must undergo metabolic activation to exert its cytotoxic effects, is a second line drug against tuberculosis, a disease that infects more than a third of the world's population. It has been proposed, on the basis of genetic experiments, that ETA is activated in Mycobacterium tuberculosis by the protein encoded by the gene Rv3854c (DeBarber, A. E., Mdluli, K., Bosman, M., Bekker, L.-G., and Barry, C. E., III (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 9677-9682; Baulard, A. R., Betts, J. C., Engohang-Ndong, J., Quan, S., McAdam, R. A., Brennan, P. J., Locht, C., and Besra, G. S. (2000) J. Biol. Chem. 275, 28326-28331). We report here the expression, purification, and characterization of the protein encoded by this gene. Our results establish that the enzyme (EtaA) is an FAD-containing enzyme that oxidizes ETA to the corresponding S-oxide. The S-oxide, which has a similar biological activity as ETA, is further oxidized by EtaA to 2-ethyl-4-amidopyridine, presumably via the unstable doubly oxidized sulfinic acid intermediate. This flavoenzyme also oxidizes thiacetazone, thiobenzamide, and isothionicotinamide and thus is probably responsible, as suggested by the observation of crossover resistance, for the oxidative activation of other thioamide antitubercular drugs.

* This work was supported by National Institutes of Health Grant GM56531.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Both authors contributed equally to this work.

§ To whom correspondence should be addressed: School of Pharmacy, S-926, University of California, San Francisco, CA 94143-0446. Fax: 415-502-4728; E-mail: ortiz@cgl.ucsf.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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