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Open AccessArticle

Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450

1
Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
2
Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Research Center Jülich, 52428 Jülich, Germany
3
JuStruct: Jülich Center for Structural Biology, Research Center Jülich, 52428 Jülich, Germany
4
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141 Minsk, Belarus
5
Grenoble Alpes University, CNRS, Inria, Grenoble INP, LJK, 38000 Grenoble, France
6
Department of Proteomic Research and Mass Spectrometry, Institute of Biomedical Chemistry, 119435 Moscow, Russia
7
R&D Department, MT-Medicals LLC, 121205 Moscow, Russia
8
Center for Computational and Data-Intensive Science and Engineering (CDISE), Skolkovo Institute of Science and Technology, 121205 Moscow, Russia
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Current affiliation includes ESRF—The European Synchrotron, 38000 Grenoble, France.
§
Current address: MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
Int. J. Mol. Sci. 2020, 21(20), 7683; https://doi.org/10.3390/ijms21207683
Received: 5 October 2020 / Revised: 12 October 2020 / Accepted: 14 October 2020 / Published: 16 October 2020
(This article belongs to the Section Molecular Biophysics)
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. View Full-Text
Keywords: cytochrome P450; crystal structure; Mycobacterium tuberculosis; SQ109; CYP124 cytochrome P450; crystal structure; Mycobacterium tuberculosis; SQ109; CYP124
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Bukhdruker, S.; Varaksa, T.; Grabovec, I.; Marin, E.; Shabunya, P.; Kadukova, M.; Grudinin, S.; Kavaleuski, A.; Gusach, A.; Gilep, A.; Borshchevskiy, V.; Strushkevich, N. Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450. Int. J. Mol. Sci. 2020, 21, 7683.

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