Trypanosoma brucei type-1 nitroreductase (TbNTR)

Trypanosoma brucei type-1 nitroreductase (TbNTR) is a key enzyme in the parasite Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (sleeping sickness). It is an oxygen-insensitive, FMN-dependent enzyme that functions as an oxidoreductase, potentially acting as an NADH:ubiquinone oxidoreductase in the parasite's mitochondrion. TbNTR is primarily known for its role in the bioactivation of nitroheterocyclic prodrugs such as nifurtimox and fexinidazole. The enzyme catalyzes the two-electron reduction of the nitro group on these drugs, leading to the formation of cytotoxic metabolites, such as unsaturated open-chain nitriles, which inhibit parasite growth. Because this enzyme is absent in humans, it provides a basis for the selective toxicity of these drugs against the parasite. However, loss or downregulation of TbNTR is a major mechanism of drug resistance, leading to cross-resistance between different nitro-based therapies.

Other names

TbNTRNTRType I nitroreductaseNADH-dependent nitroreductaseNitroreductase 1TbNTR1

Reductive activation of nitroheterocyclic prodrugs via a two-electron reduction process, leading to the formation of cytotoxic metabolites such as unsaturated open-chain nitriles or hydroxylamines that cause cellular damage and parasite death.