2xyo
Structural basis for a new tetracycline resistance mechanism relying on the TetX monooxygenase
Structural highlights
FunctionTETX_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 PubMedThe 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. See AlsoReferences
| ||||||||||||||||||||
