Decaprenylphosphoryl-beta-D-ribofuranose 2-epimerase (DprE)

Decaprenylphosphoryl-beta-D-ribofuranose 2-epimerase is an essential heterodimeric enzyme complex, composed of the subunits DprE1 and DprE2, found in Mycobacterium tuberculosis and related species [1, 4, 10]. It catalyzes the two-step epimerization of decaprenylphosphoryl-beta-D-ribose (DPR) into decaprenylphosphoryl-beta-D-arabinofuranose (DPA), which serves as the sole donor of arabinofuranosyl residues for the synthesis of the mycobacterial cell wall components arabinogalactan and lipoarabinomannan [2, 5, 8]. Because this pathway is critical for maintaining the structural integrity of the bacterial cell wall and has no human ortholog, it is a highly attractive target for antitubercular drug development [2, 3]. Inhibition of the DprE1 subunit, particularly by covalent suicide inhibitors like benzothiazinones, leads to the depletion of DPA, resulting in cell wall defects, bacterial lysis, and death [3, 11]. Several DprE1 inhibitors, including Macozinone and BTZ043, are currently in clinical trials to treat both drug-sensitive and multidrug-resistant tuberculosis [1, 10]. However, the emergence of resistance through specific active-site mutations, such as at the Cys387 residue, remains a significant therapeutic challenge [2, 6]. The enzyme's unique mechanism and essentiality make it a cornerstone of modern efforts to develop shorter and more effective regimens for tuberculosis [3, 13].

Other names

Decaprenylphosphoryl-beta-D-ribose 2'-epimeraseDprE1-DprE2 complexDecaprenylphosphoribose 2'-epimeraseDecaprenylphosphoryl-beta-D-ribofuranose 2'-epimeraseDprE1DprE2

Drugs targeting this enzyme primarily inhibit the DprE1 subunit, either through covalent suicide inhibition (e.g., benzothiazinones) or non-covalent competitive binding, which prevents the synthesis of decaprenylphosphoryl arabinose (DPA) and leads to mycobacterial cell wall disruption and death [2, 3, 11].