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

Decaprenylphosphoryl-β-D-ribose 2-epimerase, primarily known by its subunit DprE1, is a flavin-dependent oxidoreductase essential for the survival of Mycobacterium tuberculosis (UniProt: P9WGI1). It catalyzes the first step in the conversion of decaprenylphosphoryl-D-ribose (DPR) to decaprenylphosphoryl-D-arabinose (DPA), which is the unique donor of arabinosyl residues for the synthesis of the mycobacterial cell wall polymers arabinogalactan and lipoarabinomannan (PubMed: 19282811, PubMed: 30858193). Because this metabolic pathway is entirely absent in humans, DprE1 represents a highly specific and potent therapeutic target for the treatment of both drug-sensitive and multi-drug-resistant tuberculosis (PubMed: 25607151). Several clinical candidates, including benzothiazinones like Macozinone and BTZ043, target DprE1 by forming a covalent bond with a critical cysteine residue in the active site, leading to the cessation of cell wall assembly and subsequent bacterial lysis (PubMed: 29339446). Additionally, non-covalent inhibitors such as TBA-7371 and OPC-167832 are currently under clinical investigation to provide alternative treatment options and overcome potential resistance mechanisms (PubMed: 31405919).

Other names

DprE1Decaprenylphosphoryl-D-ribose oxidaseRv3790DPPO

Inhibition of the flavin-dependent epimerization of decaprenylphosphoryl-D-ribose to decaprenylphosphoryl-D-arabinose, thereby blocking the synthesis of essential mycobacterial cell wall components (PubMed: 19282811).