PMID:15452119

Citation	Yang, W, Moore, IF, Koteva, KP, Bareich, DC, Hughes, DW and Wright, GD (2004) TetX is a flavin-dependent monooxygenase conferring resistance to tetracycline antibiotics. J. Biol. Chem. 279:52346-52
Abstract	The tetracycline antibiotics block microbial translation and constitute an important group of antimicrobial agents that find broad clinical utility. Resistance to this class of antibiotics is primarily the result of active efflux or ribosomal protection; however, a novel mechanism of resistance has been reported to be oxygen-dependent destruction of the drugs catalyzed by the enzyme TetX. Paradoxically, the tetX genes have been identified on transposable elements found in anaerobic bacteria of the genus Bacteroides. Overexpression of recombinant TetX in Escherichia coli followed by protein purification revealed a stoichiometric complex with flavin adenine dinucleotide. Reconstitution of in vitro enzyme activity demonstrated a broad tetracycline antibiotic spectrum and a requirement for molecular oxygen and NADPH in antibiotic degradation. The tetracycline products of TetX activity were unstable at neutral pH, but mass spectral and NMR characterization under acidic conditions supported initial monohydroxylation at position 11a followed by intramolecular cyclization and non-enzymatic breakdown to other undefined products. TetX is therefore a FAD-dependent monooxygenase. The enzyme not only catalyzed efficient degradation of a broad range of tetracycline analogues but also conferred resistance to these antibiotics in vivo. This is the first molecular characterization of an antibiotic-inactivating monooxygenase, the origins of which may lie in environmental bacteria.
Links	PubMed Online version:10.1074/jbc.M409573200
Keywords	Bacterial Proteins/genetics; Bacterial Proteins/metabolism; Bacteroides fragilis/drug effects; Bacteroides fragilis/enzymology; Bacteroides fragilis/genetics; Escherichia coli/genetics; Flavoproteins/genetics; Flavoproteins/metabolism; Kinetics; Nuclear Magnetic Resonance, Biomolecular; Oxygenases/genetics; Oxygenases/metabolism; Oxytetracycline/chemistry; Oxytetracycline/metabolism; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Tetracycline Resistance/genetics
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
BACFG:TETX		GO:0043643: tetracycline metabolic process	ECO:0000314:		P		Figure 6 shows that Tetx gene product disrupts oxytetracycline	complete

References

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