Brecik Miroslav, Centárová Ivana, Mukherjee Raju, Kolly Gaëlle S, Huszár Stanislav, Bobovská Adela, Kilacsková Emöke, Mokošová Veronika, Svetlíková Zuzana, Šarkan Michal, Neres João, Korduláková Jana, Cole Stewart T, Mikušová Katarína
†Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia.
‡Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
ACS Chem Biol. 2015 Jul 17;10(7):1631-6. doi: 10.1021/acschembio.5b00237. Epub 2015 Apr 29.
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.
黄素酶DprE1催化癸异戊二烯基磷酸-d-阿拉伯糖（DPA）途径中的关键差向异构化步骤，该途径对分枝杆菌细胞壁生物合成至关重要，并且是几种新型结核病候选药物的作用靶点。在此，我们通过用DPA前体进行差异放射性标记和高分辨率荧光显微镜观察，揭示了DprE1意外的胞外定位以及DPA的周质合成。总体而言，这解释了DprE1的易损性以及最佳抑制剂的显著效力。
