Xanthates: Metabolism by Flavoprotein-Containing Monooxygenases and Antimycobacterial Activity

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Stanislav G YanevPaul R Ortiz de Montellano

Abstract

Ethionamide (ETH) plays a central role in the treatment of tuberculosis in patients resistant to the first-line drugs. The ETH, thioamide, and thiourea class of antituberculosis agents are prodrugs that are oxidatively converted to their active S-oxides by the mycobacterial flavin-dependent monooxygenase (EtaA) of Mycobacterium tuberculosis, thus initiating the chain of reactions that result in inhibition of mycolic acid biosynthesis and cell lysis. As part of a search for new lead candidates, we report here that several xanthates are oxidized by purified EtaA to S-oxide metabolites (perxanthates), which are implicated in the antimycobacterial activity of these compounds. This process, which is analogous to that responsible for activation of ETH, is also catalyzed by human flavoprotein monooxygenase 3. EtaA was not inhibited in a time-dependent manner during the reaction. Xanthates with longer alkyl chains were oxidized more efficiently. EtaA oxidized octyl-xanthate (Km = 5 µM; Vmax = 1.023 nmolP/min; kcat = 5.2 molP/min/molE) more efficiently than ETH (194 µM; 1.46 nmolP/min; 7.73 nmolP/min/molE, respectively). Furthermore, the in vitro antimycobacterial activity of four xanthates against M. tuberculosis H37Hv was higher (mini...Continue Reading

References

Apr 28, 1995·Chemico-biological Interactions·L L Poulsen, D M Ziegler
Jun 28, 2000·The Journal of Biological Chemistry·A R BaulardG S Besra
Dec 18, 2001·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sharon K KruegerDavid E Williams
Feb 2, 2002·The Journal of Biological Chemistry·Tommaso A VannelliPaul R Ortiz de Montellano
Oct 16, 2003·The Journal of Biological Chemistry·Benjawan PhetsuksiriPatrick J Brennan
Jan 13, 2006·Annual Review of Pharmacology and Toxicology·John R Cashman, Jun Zhang
Mar 21, 2006·Chemical Research in Toxicology·Lian Qian, Paul R Ortiz de Montellano
Aug 10, 2006·The Journal of Antimicrobial Chemotherapy·Xavier HanoulleAlain R Baulard
Sep 3, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Robert R ReddyJohn R Cashman
Sep 25, 2010·Chemico-biological Interactions·Clinton R Nishida, Paul R Ortiz de Montellano
Nov 22, 2011·Neurochemical Research·Rao Muralikrishna AdibhatlaA Gusain
Sep 30, 2016·Expert Opinion on Drug Metabolism & Toxicology·Ian R Phillips, Elizabeth A Shephard
Oct 8, 2016·Organic & Biomolecular Chemistry·Julie LabordeVania Bernardes-Génisson

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Citations

Aug 14, 2019·Archives of Biochemistry and Biophysics·Dustin Duncan, Karine Auclair

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