TY  - JOUR
AU  - Bukhdruker, Sergey
AU  - Varaksa, Tatsiana
AU  - Grabovec, Irina
AU  - Marin, Egor
AU  - Shabunya, Polina
AU  - Kadukova, Maria
AU  - Grudinin, Sergei
AU  - Kavaleuski, Anton
AU  - Gusach, Anastasiia
AU  - Gilep, Andrei
AU  - Borshchevskiy, Valentin
AU  - Strushkevich, Natallia
TI  - Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450
JO  - International journal of molecular sciences
VL  - 21
IS  - 20
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - FZJ-2020-04074
SP  - 7683 -
PY  - 2020
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 33081390
UR  - <Go to ISI:>//WOS:000585770700001
DO  - DOI:10.3390/ijms21207683
UR  - https://juser.fz-juelich.de/record/885766
ER  -