Decaprenylphosphoryl-beta-D-ribose 2'-epimerase (DprE1) (DprE1)

Decaprenylphosphoryl-beta-D-ribose 2'-epimerase (DprE1) is an essential flavoenzyme in Mycobacterium tuberculosis that plays a critical role in the biosynthesis of the mycobacterial cell wall (UniProt P9WJF0). It catalyzes the first step of the epimerization of decaprenylphosphoryl-ribose (DPR) into decaprenylphosphoryl-arabinose (DPA), which serves as the sole donor of arabinofuranosyl residues for the assembly of the essential cell wall polymers arabinogalactan and lipoarabinomannan (PubMed 19299584, PubMed 22733761). Because DprE1 is indispensable for bacterial survival and has no human homolog, it is considered a highly vulnerable and validated therapeutic target for treating tuberculosis, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains (PubMed 23996170). Several classes of inhibitors, such as benzothiazinones (e.g., Macozinone) and azaindoles (e.g., TBA-7371), are currently in clinical development, acting through either covalent or non-covalent mechanisms to disrupt cell wall integrity and induce bacterial lysis (MDPI 2024). The unique presence of DprE1 in mycobacteria minimizes the risk of off-target toxicity in humans, making it a promising target for next-generation antitubercular therapy (PubMed 1.2.1).

Other names

Decaprenylphosphoryl-beta-D-ribose oxidaseDecaprenylphospho-beta-D-ribofuranose 2-dehydrogenaseDecaprenylphosphoryl-beta-D-ribofuranose 2'-epimerase subunit DprE1Decaprenyl-phosphoribose 2'-epimerase subunit 1Decaprenylphosphoryl-beta-D-ribofuranose 2'-oxidaseDecaprenylphosphoryl-beta-D-ribose 2-epimerase flavoprotein subunitRv3790

Inhibition of the DprE1 enzyme, which catalyzes the FAD-dependent oxidation of decaprenylphosphoryl-ribose (DPR) to the keto intermediate decaprenylphosphoryl-2'-keto-D-arabinose (DPX), thereby blocking the synthesis of decaprenylphosphoryl-arabinose (DPA) required for mycobacterial cell wall assembly (UniProt P9WJF0, PubMed 19299584).