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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.
Suliana Manley, Martin Weigert, Chen Zhang, Willi Leopold Stepp, Dora Mahecic, Juliette Griffie
Suliana Manley, Jenny Sülzle, Laila Abdelaziz Abdelmoniem Elfeky