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

Target: DprE1
Molecular classification: Enzyme, Epimerase, Flavoenzyme, Short-chain dehydrogenase/reductase family

Overview

Decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) is a flavoenzyme that catalyzes a key oxidative step in the biosynthesis of the mycobacterial cell wall, converting decaprenylphosphoryl-D-ribose (DPR) to a keto intermediate, which is subsequently reduced by DprE2 to yield decaprenylphosphoryl-D-arabinose (DPA)[2][4][7]. This product is an essential arabinose donor for assembling arabinogalactan and lipoarabinomannan, molecules vital for cell wall integrity and virulence[2][4][6]. DprE1 is highly conserved and essential for survival of *Mycobacterium tuberculosis*, making it one of the most promising targets for anti-tuberculosis therapeutics[3][5][7][8]. Numerous small molecule inhibitors have been developed to block DprE1, many acting via both covalent and non-covalent mechanisms, some progressing to clinical trials. Therapeutic challenges include the emergence of resistance and optimizing drug specificity and safety[6][7].

Other names: Decaprenylphospho-beta-D-ribofuranose 2-oxidaseDecaprenylphosphoryl-D-ribose epimeraseRv3790 (gene in *M. tuberculosis*)Decaprenylphosphoryl-D-ribose oxidase

Mechanism of action

Covalent inhibition of DprE1 (e.g., BTZs form covalent bonds with the enzyme) Non-covalent inhibition (e.g., quinoxaline derivatives interact by hydrogen bonding) Blockade of cell wall biosynthesis, leading to mycobacterial cell lysis

Biological functions

Cell wall biosynthesis (production of lipoarabinomannan and arabinogalactan for mycobacterial cell wall)Epimerization of decaprenylphosphoryl-D-ribose to decaprenylphosphoryl-D-arabinoseOxidation-reduction reactions

Disease associations

Infection (especially tuberculosis caused by *Mycobacterium tuberculosis*)

Safety considerations

Emergence of resistant mycobacterial strains to DprE1 inhibitorsPotential for mutagenicity with certain compound scaffolds (demonstrated in AMES assays, e.g., high mutagenicity rates in some inhibitor classes)Need for optimization to reduce off-target/host toxicities (as seen in drug development pipelines)

Interacting drugs

Benzothiazinones (BTZs, e.g. BTZ043)

5 more in the full profile.

Biomarkers

DprE1 protein expression in mycobacterial cultures (used in research and drug screening)No validated clinical biomarkers for patient selection are currently reported

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