F420-dependent deazaflavin nitroreductase (Ddn) (Ddn)

The F420-dependent deazaflavin nitroreductase (Ddn) is a specialized enzyme in Mycobacterium tuberculosis that plays a pivotal role in the activation of nitroimidazole-class antibiotics, including pretomanid and delamanid (Singh et al., 2008, Science). Ddn functions as part of a larger biochemical system that requires the deazaflavin coenzyme F420, which is maintained in its reduced state by glucose-6-phosphate dehydrogenase (Fgd1) (Manjunatha et al., 2006, PNAS). Upon binding a nitroimidazole prodrug, Ddn catalyzes a deazaflavin-dependent reduction that results in the release of reactive nitrogen species, most notably nitric oxide (NO) (Cellitti et al., 2012, ChemBioChem). This release leads to a lethal dual mechanism: the inhibition of mycolic acid biosynthesis, which compromises the bacterial cell wall, and the poisoning of the respiratory chain, which is particularly effective against non-replicating, anaerobic mycobacteria (Singh et al., 2008, Science). Because the therapeutic efficacy of these drugs is entirely dependent on this activation system, mutations in the ddn gene or the genes involved in F420 biosynthesis (fbiA, fbiB, fbiC) and recycling (fgd1) are the primary mechanisms of bacterial resistance (Stover et al., 2000, Nature). Understanding the structural and functional nuances of the Ddn-F420 system is therefore essential for monitoring drug resistance and designing more potent antitubercular therapies. Its specific expression in mycobacteria makes it an ideal target for selective toxicity, minimizing impact on host cells.

Other names

Deazaflavin-dependent nitroreductaseRv3547F420-dependent nitroreductase

Reductive activation of nitroimidazole prodrugs to release reactive nitrogen species (RNS), primarily nitric oxide, which inhibits mycolic acid synthesis and disrupts bacterial respiration.