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@ARTICLE{Bukhdruker:885766,
      author       = {Bukhdruker, Sergey and Varaksa, Tatsiana and Grabovec,
                      Irina and Marin, Egor and Shabunya, Polina and Kadukova,
                      Maria and Grudinin, Sergei and Kavaleuski, Anton and Gusach,
                      Anastasiia and Gilep, Andrei and Borshchevskiy, Valentin and
                      Strushkevich, Natallia},
      title        = {{H}ydroxylation of {A}ntitubercular {D}rug {C}andidate,
                      {SQ}109, by {M}ycobacterial {C}ytochrome {P}450},
      journal      = {International journal of molecular sciences},
      volume       = {21},
      number       = {20},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {FZJ-2020-04074},
      pages        = {7683 -},
      year         = {2020},
      abstract     = {Spreading of the multidrug-resistant (MDR) strains of the
                      one of the most harmful pathogen Mycobacterium tuberculosis
                      (Mtb) generates the need for new effective drugs. SQ109
                      showed activity against resistant Mtb and already advanced
                      to Phase II/III clinical trials. Fast SQ109 degradation is
                      attributed to the human liver Cytochrome P450s (CYPs).
                      However, no information is available about interactions of
                      the drug with Mtb CYPs. Here, we show that Mtb CYP124,
                      previously assigned as a methyl-branched lipid
                      monooxygenase, binds and hydroxylates SQ109 in vitro. A 1.25
                      Å-resolution crystal structure of the CYP124–SQ109
                      complex unambiguously shows two conformations of the drug,
                      both positioned for hydroxylation of the ω-methyl group in
                      the trans position. The hydroxylated SQ109 presumably forms
                      stabilizing H-bonds with its target, Mycobacterial membrane
                      protein Large 3 (MmpL3). We anticipate that Mtb CYPs could
                      function as analogs of drug-metabolizing human CYPs
                      affecting pharmacokinetics and pharmacodynamics of
                      antitubercular (anti-TB) drugs.},
      cin          = {IBI-7},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {552 - Engineering Cell Function (POF3-552)},
      pid          = {G:(DE-HGF)POF3-552},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {33081390},
      UT           = {WOS:000585770700001},
      doi          = {10.3390/ijms21207683},
      url          = {https://juser.fz-juelich.de/record/885766},
}