Microbial nitroreductase (NTR)

Microbial nitroreductases (NTRs) are flavin-containing enzymes, most notably from Escherichia coli (NfsB), that facilitate the reduction of nitroaromatic compounds using NAD(P)H as an electron donor (UniProt: P0AAI4). These enzymes are the cornerstone of microbial nitroreductase activation systems, which are primarily employed in Gene-Directed Enzyme Prodrug Therapy (GDEPT) to treat various cancers (Williams et al., 2015; DOI: 10.1039/C4CS00242B). In this system, a bacterial gene encoding NTR is delivered to tumor cells, where it expresses the enzyme to selectively activate prodrugs like CB1954 (Tretazicar) into potent DNA-damaging agents. This localized activation minimizes systemic toxicity while maximizing the cytotoxic effect within the tumor microenvironment. Additionally, NTR systems are utilized in biological research for conditional cell ablation and as reporters for imaging gene expression. Despite their promise, clinical application is often limited by the immunogenicity of the bacterial enzyme and the efficiency of gene delivery to the target site. The system's efficacy is also dependent on the bystander effect, where activated drug molecules diffuse to neighboring non-expressing cells to enhance tumor kill.

Other names

NfsBNfsABacterial nitroreductaseOxygen-insensitive nitroreductaseNitroreductase activation system

Microbial nitroreductases catalyze the NAD(P)H-dependent reduction of nitro groups on prodrug substrates to hydroxylamines or amines, which then act as potent cytotoxic agents, often by inducing DNA interstrand cross-linking or strand breaks (Green et al., 2011; PubMed: 21513475).