Decaprenylphosphoryl-2-keto-beta-D-erythro-pentofuranose reductase (DprE2) (DprE2)

Decaprenylphosphoryl-2-keto-beta-D-erythro-pentofuranose reductase (DprE2) is an essential enzyme in Mycobacterium tuberculosis (Mtb) that plays a critical role in the biosynthesis of the mycobacterial cell wall. It functions as part of the DprE1-DprE2 epimerase complex, which converts decaprenyl-phospho-ribose (DPR) into decaprenyl-phospho-arabinose (DPA), the essential arabinosyl donor for the synthesis of arabinogalactan and lipoarabinomannan. Because DPA is unique to mycobacteria and essential for their survival, DprE2 is a highly specific and potent therapeutic target. Recent studies have demonstrated that the nitroimidazole drugs pretomanid and delamanid, which are key components of modern multidrug-resistant tuberculosis (MDR-TB) regimens, target DprE2 after being metabolically activated into NAD-adducts. Inhibition of this enzyme leads to the depletion of cell wall precursors, resulting in bacterial lysis and death. DprE2 remains a focal point for developing next-generation antitubercular agents capable of overcoming existing drug resistance.

Other names

Rv3791Decaprenylphosphoryl-2-keto-beta-D-erythro-pentose reductaseDprE2 subunit of decaprenylphosphoribose-2'-epimerase

DprE2 catalyzes the NADH-dependent reduction of the keto intermediate decaprenyl-phospho-2'-keto-D-arabinose (DPX) to decaprenyl-phospho-arabinose (DPA). Drugs like pretomanid and delamanid act as prodrugs that are activated by the mycobacterial deazaflavin-dependent nitroreductase (Ddn) to form NAD-adducts; these active metabolites then inhibit DprE2, preventing the synthesis of essential cell wall components.