F420-dependent nitroreductase Ddn (Ddn)

F420-dependent nitroreductase Ddn (Rv3547) is a specialized enzyme in Mycobacterium tuberculosis that is essential for the activation of bicyclic nitroimidazole prodrugs, such as pretomanid and delamanid (Manjunatha et al., 2006, PubMed: 16621273). The enzyme utilizes the reduced form of the deazaflavin cofactor F420 to catalyze the reduction of the nitro group on these compounds, a process that releases reactive nitrogen species, including nitric oxide (Singh et al., 2008, PubMed: 19037252). These reactive intermediates subsequently inhibit the synthesis of mycolic acids, which are critical components of the mycobacterial cell wall, and disrupt cellular respiration under both aerobic and anaerobic conditions (Stover et al., 2000, PubMed: 10948539). Because Ddn is unique to certain bacteria and lacks a human homolog, it represents a highly specific therapeutic target for treating multi-drug-resistant tuberculosis. However, the efficacy of drugs targeting this pathway is threatened by mutations in the ddn gene or the F420 biosynthetic and recycling pathways, which are the primary drivers of clinical resistance (Cellier et al., 2017, PubMed: 28807911).

Other names

Deazaflavin-dependent nitroreductaseRv3547Nitroreductase DdnF420-dependent nitroreductase

Bioreductive activation of nitroimidazole prodrugs to release reactive nitrogen species (e.g., nitric oxide) and inhibit mycolic acid synthesis.