Flavin-containing monooxygenase EthA (EthA)

Flavin-containing monooxygenase EthA is a critical enzyme produced by Mycobacterium tuberculosis that serves as the primary activator for several second-line antitubercular prodrugs, including ethionamide and prothionamide (UniProt P9WPR1). It functions as a Baeyer-Villiger monooxygenase, utilizing FAD and NADPH to catalyze the oxidation of thioamides into their active sulfoxide derivatives (PubMed: 10629171). These active metabolites subsequently inhibit the InhA enzyme, thereby disrupting mycolic acid biosynthesis and compromising the bacterial cell wall (DrugBank DB00609). The expression of EthA is tightly controlled by the transcriptional repressor EthR; consequently, mutations in the ethA gene or overexpression of EthR are major drivers of clinical resistance to thioamide drugs (PubMed: 22307173). Beyond its role in drug activation, EthA is involved in the metabolism of various sulfur-containing compounds within the mycobacterial cell (PubMed: 11544223). Research into EthA focuses on identifying small-molecule boosters that can inhibit EthR to increase EthA expression, thereby restoring or enhancing the efficacy of ethionamide in drug-resistant tuberculosis strains (PubMed: 23303604). This strategy aims to overcome the low natural expression of EthA which often limits the therapeutic window of its substrates.

Other names

Ethionamide monooxygenaseRv3854cBaeyer-Villiger monooxygenase EthAFMO

EthA acts as an activating enzyme that converts thioamide prodrugs into their active antimicrobial forms through oxidative metabolism.