2y6r

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Structure of the TetX monooxygenase in complex with the substrate 7- chlortetracycline

Structural highlights

2y6r is a 4 chain structure with sequence from Bacteroides thetaiotaomicron. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.1Å
Ligands:CTC, FAD, SO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

The flavin-dependent monooxygenase TetX confers resistance to all clinically relevant tetracyclines, including the recently approved, broad-spectrum antibiotic tigecycline (Tygacil(R)) which is a critical last-ditch defense against multidrug-resistant pathogens. TetX represents the first resistance mechanism against tigecycline, which circumvents both the tet-gene encoded resistances, relying on active efflux of tetracyclines, and ribosomal protection proteins. The alternative enzyme-based mechanism of TetX depends on regioselective hydroxylation of tetracycline antibiotics to 11a-hydroxy-tetracyclines. Here, we report the X-ray crystallographic structure determinations at 2.1A resolution of native TetX from Bacteroides thetaiotaomicron and its complexes with tetracyclines. Our crystal structures explain the extremely versatile substrate diversity of the enzyme and provide a first step towards the rational design of novel tetracycline derivatives to counter TetX-based resistance prior to emerging clinical observations.

Structural basis for a new tetracycline resistance mechanism relying on the TetX monooxygenase.,Volkers G, Palm GJ, Weiss MS, Wright GD, Hinrichs W FEBS Lett. 2011 Mar 16. PMID:21402075[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
11 reviews cite this structure
Ribosome-targeting antibiotics and mechanisms of bacterial resistance.
Wilson et al. (2014)
10 more
27 other articles
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See Also

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
  6. ↑ Volkers G, Palm GJ, Weiss MS, Wright GD, Hinrichs W. Structural basis for a new tetracycline resistance mechanism relying on the TetX monooxygenase. FEBS Lett. 2011 Mar 16. PMID:21402075 doi:10.1016/j.febslet.2011.03.012

Contents


PDB ID 2y6r

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