4guv

Structural highlights

Function

TETX_BACT4 An FAD-requiring monooxygenase active on tetracycline antibiotic derivatives, which leads to their inactivation (PubMed:15452119, PubMed:16128584). Hydroxylates carbon 11a of oxytetracycline and tigecycline (PubMed:15452119, PubMed:26097034). Acts on many tetracycline analogs (chlorotetracycline, demeclocycline, doxycycline, minocycline, oxytetracyclinee), probably by monooxygenization (PubMed:15452119, PubMed:16128584). Tigecycline, a new generation tetracycline antibiotic, is rendered less effective against E.coli by this monooxygenation, is much weaker at inhibiting translation in vitro and binds Mg(2+) considerably less well (PubMed:16128584, PubMed:26097034). Expression in E.coli BW25113 reduces its growth rate about 5%. The reaction probably proceeds by FAD reduction by NADPH and, second, hydroxylation of antibiotic in a ping-pong mechanism (PubMed:23236139). Degrades chlortetracycline, probably by monooxygenation (PubMed:15452119, PubMed:28481346). Slowly oxidizes anhydrotetracycline, the final substrate in tetracycline biosynthesis (PubMed:26097034).[HAMAP-Rule:MF_00845]^{[1] [2] [3] [4] [5]}

References

1. ↑ Yang W, Moore IF, Koteva KP, Bareich DC, Hughes DW, Wright GD. TetX is a flavin-dependent monooxygenase conferring resistance to tetracycline antibiotics. J Biol Chem. 2004 Dec 10;279(50):52346-52. doi: 10.1074/jbc.M409573200. Epub 2004, Sep 27. PMID:15452119 doi:http://dx.doi.org/10.1074/jbc.M409573200
2. ↑ Moore IF, Hughes DW, Wright GD. Tigecycline is modified by the flavin-dependent monooxygenase TetX. Biochemistry. 2005 Sep 6;44(35):11829-35. doi: 10.1021/bi0506066. PMID:16128584 doi:http://dx.doi.org/10.1021/bi0506066
3. ↑ Walkiewicz K, Benitez Cardenas AS, Sun C, Bacorn C, Saxer G, Shamoo Y. Small changes in enzyme function can lead to surprisingly large fitness effects during adaptive evolution of antibiotic resistance. Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21408-13. doi:, 10.1073/pnas.1209335110. Epub 2012 Dec 10. PMID:23236139 doi:http://dx.doi.org/10.1073/pnas.1209335110
4. ↑ Forsberg KJ, Patel S, Wencewicz TA, Dantas G. The Tetracycline Destructases: A Novel Family of Tetracycline-Inactivating Enzymes. Chem Biol. 2015 Jul 23;22(7):888-97. doi: 10.1016/j.chembiol.2015.05.017. Epub, 2015 Jun 18. PMID:26097034 doi:http://dx.doi.org/10.1016/j.chembiol.2015.05.017
5. ↑ Park J, Gasparrini AJ, Reck MR, Symister CT, Elliott JL, Vogel JP, Wencewicz TA, Dantas G, Tolia NH. Plasticity, dynamics, and inhibition of emerging tetracycline resistance enzymes. Nat Chem Biol. 2017 May 8. doi: 10.1038/nchembio.2376. PMID:28481346 doi:http://dx.doi.org/10.1038/nchembio.2376