{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:01:45Z","timestamp":1790935305536,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2011,11,3]],"date-time":"2011-11-03T00:00:00Z","timestamp":1320278400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Microbiology"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>NADH pyrophosphatase (NudC) catalyses the hydrolysis of NAD(H) to AMP and NMN(H) [nicotinamide mononucleotide (reduced form)]. NudC multiple sequence alignment reveals that homologues from most <jats:italic>Mycobacterium tuberculosis<\/jats:italic> isolates, but not other mycobacterial species, have a polymorphism at the highly conserved residue 237. To elucidate the functional significance of this polymorphism, comparative analyses were performed using representative NudC isoforms from <jats:italic>M.\u2003tuberculosis<\/jats:italic> H37Rv (NudC<jats:sub>Rv<\/jats:sub>) and <jats:italic>M.\u2003bovis<\/jats:italic> BCG (NudC<jats:sub>BCG<\/jats:sub>). Biochemical analysis showed that the P237Q polymorphism prevents dimer formation, and results in a loss of enzymatic activity. Importantly, NudC<jats:sub>BCG<\/jats:sub> was found to degrade the active forms of isoniazid (INH), INH\u2010NAD and ethionamide (ETH), ETH\u2010NAD. Consequently, overexpression of NudC<jats:sub>BCG<\/jats:sub> in <jats:italic>Mycobacterium smegmatis<\/jats:italic> mc<jats:sup>2<\/jats:sup>155 and <jats:italic>M.\u2003bovis<\/jats:italic> BCG resulted in a high level of resistance to both INH and ETH. Further genetic studies showed that deletion of the <jats:italic>nudC<\/jats:italic> gene in <jats:italic>M.\u2003smegmatis<\/jats:italic> mc<jats:sup>2<\/jats:sup>155 and <jats:italic>M.\u2003bovis<\/jats:italic> BCG resulted in increased susceptibility to INH and ETH. Moreover, inactivation of NudC in both strains caused a defect in drug tolerance phenotype for both drugs in exposure assays. Taken together, these data suggest that mycobacterial NudC plays an important role in the inactivation of INH and ETH.<\/jats:p>","DOI":"10.1111\/j.1365-2958.2011.07892.x","type":"journal-article","created":{"date-parts":[[2011,10,26]],"date-time":"2011-10-26T10:21:52Z","timestamp":1319624512000},"page":"1375-1391","source":"Crossref","is-referenced-by-count":28,"title":["Comparative analysis of mycobacterial NADH pyrophosphatase isoforms reveals a novel mechanism for isoniazid and ethionamide 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