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

Decaprenylphosphoryl-beta-D-ribose 2-epimerase is an essential enzyme complex in Mycobacterium tuberculosis, primarily represented by its druggable subunit DprE1 (decaprenylphosphoryl-beta-D-ribose oxidase) [1][3]. It catalyzes the first step in the conversion of decaprenylphosphoryl-ribose (DPR) to decaprenylphosphoryl-arabinose (DPA), which is the sole donor of arabinofuranosyl residues for the synthesis of the mycobacterial cell wall components arabinogalactan and lipoarabinomannan [2][5]. Because this pathway is absent in humans and essential for the structural integrity of the mycobacterial cell wall, it has become a major focus for the development of new anti-tuberculosis therapies [8][12]. Drugs targeting this enzyme, such as the benzothiazinone Macozinone and the carbostyril OPC-167832, work by inhibiting DprE1 either through covalent modification of a conserved cysteine residue or via non-covalent binding [4][6]. Covalent inhibitors often act as suicide substrates, where the enzyme's own FAD cofactor activates the drug into a reactive species [2][6]. The resulting depletion of DPA leads to cell wall defects, bacterial lysis, and death, providing a potent mechanism against both drug-sensitive and multi-drug-resistant tuberculosis strains [1][10].

Other names

DprE1Decaprenylphosphoryl-beta-D-ribose oxidaseRv3790Decaprenylphosphoryl-beta-D-ribofuranose 2'-epimeraseDPR 2-epimerase

Inhibition of the epimerization of decaprenylphosphoryl-ribose (DPR) to decaprenylphosphoryl-arabinose (DPA), thereby blocking the synthesis of essential mycobacterial cell wall components and leading to bacterial lysis [1][2][4].