Decaprenylphosphoryl-beta-D-ribose 2'-epimerase subunit DprE2 (DprE2)

Decaprenylphosphoryl-beta-D-ribose 2'-epimerase subunit DprE2 is an essential enzyme in the cell wall biosynthetic pathway of mycobacteria, notably Mycobacterium tuberculosis. It partners with DprE1, forming a two-component epimerase complex that catalyzes the sequential conversion of decaprenylphosphoryl-D-ribose (DPR) to decaprenylphosphoryl-D-arabinose (DPA), a critical donor of arabinose for the assembly of cell wall arabinogalactan[3][5][7]. DprE2 belongs to the short-chain dehydrogenase/reductase (SDR) family, containing a conserved catalytic triad (Ser-Tyr-Lys)[1][2]. It requires NADH or NADPH as cofactors for its enzymatic reduction step[5][6]. DprE2 has emerged as a molecular target for new anti-tubercular drugs, such as pretomanid and delamanid, which inhibit its function by forming an NAD-adduct after drug activation[5][6]. Because it is essential to mycobacterial survival and not found in humans, DprE2 is a high-priority target in tuberculosis drug development[5][3][7]. Resistance can arise via mutations, and efficacy depends on proper drug and cofactor activation.

Other names

DprE2Decaprenylphosphoryl-D-ribose 2'-epimerase subunit DprE2Rv3791 (gene locus in Mycobacterium tuberculosis)Decaprenylphosphoryl-beta-D-ribose epimerase subunit DprE2

Formation of NAD-adduct: activated forms of pretomanid and delamanid generate NAD-adducts that directly inhibit DprE2 enzymatic activity Prodrug activation: drugs require activation within mycobacteria to produce a metabolite capable of inhibiting DprE2