The Antituberculosis Drug Ethionamide Is Activated by a Flavoprotein Monooxygenase

Vannelli, Tommaso A.; Dykman, Alina; Montellano, Paul R. Ortiz de

doi:10.1074/jbc.m110751200

Cited by 204 publications

(225 citation statements)

References 24 publications

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“…However, both the structure/function properties of EtaA, the FMO from M. tuberculosis, and the physiological functions of this enzyme are still largely unknown. Some thiocarbonyl compounds in addition to ETA, notably thiobenzamide and isothionicotinamide, have been examined as substrates for EtaA and only sulfoxide-like products have been identified (16). We have shown here in vitro that oxidation of TAZ by EtaA in the presence of NADPH yields a sulfinic acid and a carbodiimide as the final metabolites.…”

Section: Discussionmentioning

confidence: 92%

“…We have shown here in vitro that oxidation of TAZ by EtaA in the presence of NADPH yields a sulfinic acid and a carbodiimide as the final metabolites. The K m , V max , and k cat values for the EtaA-catalyzed oxidation indicate that TAZ, like ETA (16), is a reasonable substrate for the enzyme.…”

Section: Discussionmentioning

confidence: 93%

“…The expression and purification of EtaA were performed as previously reported (16). Transformation of the Rv3854c gene into commercial (Invitrogen) competent DH5α…”

Section: Expression and Purification Of Etaamentioning

confidence: 99%

“…The role of EtaA in activation of ETA was confirmed by the finding that overexpression of EtaA in Mycobacterium smegmatis resulted in ETA-hypersensitive mycobacteria. In 2002, Vannelli et al successfully expressed, purified, and characterized the EtaA protein (16). These authors demonstrated in vitro that EtaA, in the presence of NADPH, catalyzes two oxidations of ETA, first to the thioamide S-oxide and subsequently to 2-ethyl-4-carboxamidopyridine ( Figure 1 Very limited information is available concerning the metabolism and biological action of TAZ.…”

Section: Introductionmentioning

confidence: 99%

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Oxidative Activation of Thiacetazone by the Mycobacterium tuberculosis Flavin Monooxygenase EtaA and Human FMO1 and FMO3

Qian

Montellano

2006

Chem. Res. Toxicol.

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Thiacetazone (TAZ) and ethionamide (ETA) are, respectively, thiourea and thioamide-containing second line antitubercular prodrugs for which there is an extensive clinical history of cross-resistance in Mycobacterium tuberculosis. EtaA, a recently identified flavin-containing monooxygenase (FMO), is responsible for the oxidative activation of ETA in M. tuberculosis. We report here that EtaA also oxidizes TAZ and identify a sulfinic acid and a carbodiimide as the isolable metabolites. Both of these metabolites are derived from an initial sulfenic acid intermediate. Oxidation of TAZ by EtaA at basic pH favors formation of the carbodiimide, whereas neutral or acidic conditions favor formation of the sulfinic acid. The same metabolites are formed from TAZ by human FMO1 and FMO3. The sulfenic acid and carbodiimide metabolites, but not the sulfinic acid product, readily react with glutathione, the first to regenerate the parent drug and the second to give a glutathione adduct. These reactions that may contribute to the antitubercular activity and/or toxicity of TAZ.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 93%

“…The expression and purification of EtaA were performed as previously reported (16). Transformation of the Rv3854c gene into commercial (Invitrogen) competent DH5α…”

Section: Expression and Purification Of Etaamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oxidative Activation of Thiacetazone by the Mycobacterium tuberculosis Flavin Monooxygenase EtaA and Human FMO1 and FMO3

Qian

Montellano

2006

Chem. Res. Toxicol.

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“…Recently, the laboratory of Dr. Paul Ortiz de Montellano demonstrated that ethionamide is a prodrug that must be S-oxygenated by an FMO in the target organism, Mycobacterium tuberculosis, to exert its effect (Vannelli et al, 2002). The metabolic activation of ethionamide by the bacterial FMO is the same as the mammalian FMO activation of thiobenzamide to produce hepatotoxic sulfinic and sulfinic acid metabolites.…”

Section: Role Of Flavin-containing Monooxygenase In Metabolism Of S-cmentioning

confidence: 99%

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Krueger

Williams

2005

Pharmacology & Therapeutics

504

444

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Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "softnucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics.In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences.The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.

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Antitubercular Agents

Aldrich

Boshoff

2010

Burger's Medicinal Chemistry and Drug Discovery

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The Antituberculosis Drug Ethionamide Is Activated by a Flavoprotein Monooxygenase

Abstract: 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.

Cited by 204 publications

References 24 publications

Oxidative Activation of Thiacetazone by the Mycobacterium tuberculosis Flavin Monooxygenase EtaA and Human FMO1 and FMO3

Oxidative Activation of Thiacetazone by the Mycobacterium tuberculosis Flavin Monooxygenase EtaA and Human FMO1 and FMO3

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Antitubercular Agents

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