title: DprE1 Is a Vulnerable Tuberculosis Drug Target Due to Its Cell Wall Localization.
abstract: The flavo-enzyme DprE1 catalyzes a key epimerization step in the decaprenyl-phosphoryl d-arabinose (DPA) pathway, which is essential for mycobacterial cell wall biogenesis and targeted by several new tuberculosis drug candidates. Here, using differential radiolabeling with DPA precursors and high-resolution fluorescence microscopy, we disclose the unexpected extracytoplasmic localization of DprE1 and periplasmic synthesis of DPA. Collectively, this explains the vulnerability of DprE1 and the remarkable potency of the best inhibitors.
authors.affiliation: †Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Brecik
authors.affiliation: †Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Centárová
authors.affiliation: ‡Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Raju
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: ‡Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Gaëlle S
authors.initials: GS
authors.lastname: Kolly
authors.affiliation: †Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Huszár
authors.affiliation: †Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia.
authors.forename: Adela
authors.initials: A
authors.lastname: Bobovská
authors.affiliation: †Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia.
authors.forename: Emöke
authors.initials: E
authors.lastname: Kilacsková
authors.affiliation: †Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia.
authors.forename: Veronika
authors.initials: V
authors.lastname: Mokošová
authors.affiliation: †Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Svetlíková
authors.affiliation: †Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia.
authors.forename: Michal
authors.initials: M
authors.lastname: Šarkan
authors.affiliation: ‡Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: João
authors.initials: J
authors.lastname: Neres
authors.affiliation: †Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia.
authors.forename: Jana
authors.initials: J
authors.lastname: Korduláková
authors.affiliation: ‡Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
authors.affiliation: †Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia.
authors.forename: Katarína
authors.initials: K
authors.lastname: Mikušová
mesh_terms: D000429:Alcohol Oxidoreductases / Q000032:analysis* / Q000378:metabolism*; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000032:analysis* / Q000378:metabolism*; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D000429:Alcohol Oxidoreductases; C583625:DprE1 protein, Mycobacterium tuberculosis