Mycolic acid synthesis enzyme DprE2

DprE2 (decaprenylphosphoryl-β-D-ribose 2′-epimerase subunit 2) is an essential enzyme in the cell wall biosynthesis pathway of *Mycobacterium tuberculosis* (Mtb). It forms a heteromeric complex with DprE1, together catalyzing a two-step epimerization reaction crucial for the production of decaprenylphosphoryl-D-arabinose (DPA), which is the only known precursor for arabinofuranosyl residues incorporated into key mycobacterial cell wall components such as arabinogalactan and lipoarabinomannan. DprE1 oxidizes decaprenylphosphoryl-β-D-ribose (DPR) to form decaprenylphosphoryl-D-2-keto-ribose (DPX) while DprE2 reduces DPX to produce decaprenylphosphoryl-D-arabinose (DPA). The product, DPA, is essential for synthesizing arabinogalactan—a major polysaccharide in the Mtb cell wall, making the epimerase complex indispensable for bacterial viability and pathogenicity. Clinically relevant anti-tubercular drugs such as delamanid and pretomanid target this pathway, binding directly to DprE2, inhibiting its function. Inhibition results in reduced production of arabinogalactan, indirectly affecting mycolic acid attachment sites on the cell envelope.

Inhibition of DprE2, leading to reduced production of decaprenylphosphoryl-D-arabinose (DPA) and subsequent disruption of arabinogalactan synthesis.